Physiol Rev 86: 747– 803, 2006;
doi:10.1152/physrev.00036.2005.
Physiology of Local Renin-Angiotensin Systems
MARTIN PAUL, ALI POYAN MEHR, AND REINHOLD KREUTZ
Institute of Clinical Pharmacology and Toxicology, Campus Benjamin Franklin,
Charité-University Medicine Berlin, Berlin, Germany
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I. Local Renin-Angiotensin Systems
A. Definition of local RAS
B. Components of the local RAS
II. Localization and Functional Aspects
A. Heart
B. Vasculature
C. Nervous system
D. Reproductive tract
E. Skin
F. Digestive organs
G. Sensory organs
H. Lymphatic tissue
I. Adipose tissue
III. Prenatal Development
IV. Summary
Paul, Martin, Ali Poyan Mehr, and Reinhold Kreutz. Physiology of Local Renin-Angiotensin Systems. Physiol
Rev 86: 747– 803, 2006; doi:10.1152/physrev.00036.2005.—Since the first identification of renin by Tigerstedt and
Bergmann in 1898, the renin-angiotensin system (RAS) has been extensively studied. The current view of the system
is characterized by an increased complexity, as evidenced by the discovery of new functional components and
pathways of the RAS. In recent years, the pathophysiological implications of the system have been the main focus
of attention, and inhibitors of the RAS such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin
(ANG) II receptor blockers have become important clinical tools in the treatment of cardiovascular and renal
diseases such as hypertension, heart failure, and diabetic nephropathy. Nevertheless, the tissue RAS also plays an
important role in mediating diverse physiological functions. These focus not only on the classical actions of ANG on
the cardiovascular system, namely, the maintenance of cardiovascular homeostasis, but also on other functions.
Recently, the research efforts studying these noncardiovascular effects of the RAS have intensified, and a large body
of data are now available to support the existence of numerous organ-based RAS exerting diverse physiological
effects. ANG II has direct effects at the cellular level and can influence, for example, cell growth and differentiation,
but also may play a role as a mediator of apoptosis. These universal paracrine and autocrine actions may be
important in many organ systems and can mediate important physiological stimuli. Transgenic overexpression and
knock-out strategies of RAS genes in animals have also shown a central functional role of the RAS in prenatal
development. Taken together, these findings may become increasingly important in the study of organ physiology
but also for a fresh look at the implications of these findings for organ pathophysiology.
I. LOCAL RENIN-ANGIOTENSIN SYSTEMS
A. Definition of Local RAS
In its “textbook” definition, the renin-angiotensin system (RAS) is a peptidergic system with endocrine characteristics. The substrate of the system, angiotensinogen,
an ␣-glycoprotein, is released from the liver (152, 250,
444) and is cleaved in the circulation by the enzyme renin
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that is secreted from the juxtaglomerular apparatus of the
kidney (245, 250, 540, 631) to form the decapeptide angiotensin (ANG) I. ANG I is then activated to the octapeptide ANG II by angiotensin converting enzyme (ACE), a
membrane-bound metalloproteinase, which is predominantly expressed in high concentrations on the surface of
endothelial cells in the pulmonary circulation (109, 111,
250, 486, 664, 665, 767). ANG II, considered the main
effector peptide of the RAS, is then acting on specific
0031-9333/06 $18.00 Copyright © 2006 the American Physiological Society
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Physiol Rev • VOL
cardiac renin were based on artifacts due to contamination with plasma renin or active renin uptake from the
circulation. This issue should not threaten the concept of
local RAS, since either mechanism could contribute to
local ANG synthesis and actions. Modern concepts of the
tissue RAS, therefore, are function oriented.
B. Components of the Local RAS
The characteristics and regulatory significance of
long-known components of the tissue RAS such as renin,
angiotensinogen, ACE, and ANG peptides (ANG I and II)
have been reviewed extensively (27, 172, 177, 381, 415,
482, 527, 727) and will not be addressed further in this
section. The focus of this section is set rather on recent
discoveries concerning new factors and pathways involved in ANG biosynthesis and function.
1. Prorenin and renin binding and receptors
The binding of prorenin and renin to the cell surface
in tissues is of pivotal importance with regard to the
physiology of local RAS at the tissue level in organs, since
it provides a mechanism to generate ANG II locally in
excess of the ANG II that is produced in plasma. Previously, it was suggested that binding of prorenin and/or
renin is responsible for uptake into tissues (5). It was
postulated that this mechanism (which is known also for
other enzymes) rather than de novo renin biosynthesis at
obscure local sites is responsible for local actions of ANG
II. Our understanding of the potential role of prorenin and
renin binding has been significantly expanded by the characterization of several proteins capable of binding prorenin and/or renin (87, 315, 488, 490).
The mannose-6-phosphate receptor (M6P) has been
shown to be involved in renin and prorenin uptake into
cells (132, 602, 733, 737). The cation-independent M6P is
directly coupled to G proteins (225, 603) and binds not
only prorenin and renin but is in general involved in
transport of proteins containing M6P residues; it leads
also to insulin-like growth factor II internalization and
inactivation (225). M6P was shown to bind renin and
prorenin on neonatal rat cardiac myocytes (601) and on
human endothelial cells (5). Only glycosylated prorenin
and renin are bound by this receptor, and binding is
followed by internalization and activation by proteolytic
cleavage and subsequent immediate degradation of renin
as demonstrated on cardiac cells (488, 601). Particularly
studies in endothelial cells indicated that uptake of prorenin by M6P represents a clearance mechanism (733).
The role as a clearance receptor on cardiac myocytes is
also supported by the finding that intracellular ANG generation could not be demonstrated following (pro)renin
uptake in these cells (315, 603). In addition, Peters et al.
(542) provided evidence for the existence for a prorenin
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receptors, for example, to induce vasoconstriction by
interacting with ANG receptors on vascular smooth muscle cells or by stimulating the release of aldosterone from
the adrenal cortex (250, 285, 562).
This view of the RAS, which has been generated by
accumulated evidence over decades, had to be expanded
significantly by more recent findings that increased the
complexity of the system. Different ANG receptors (AT1,
AT2, AT4) and signal transduction pathways involved have
been characterized (142, 306, 462, 505, 604, 639, 681, 691,
712, 724, 785). Moreover, additional truncated peptides
such as ANG-(1O7) have been identified (200, 310, 420,
595, 769), and alternative pathways of ANG II formation,
for example, by the serine protease chymase (which can
also cleave ANG I to form ANG II), have been proposed
(20, 728, 730, 781).
The resulting change of our view of the RAS has been
the introduction of the concept of “local” or “tissue” renin
angiotensin systems (178, 415, 527). This concept was
based on findings of RAS components in “unlikely” places
(such as the “kidney enzyme” renin in the brain) where
the endocrine actions of the system could not explain the
findings (219, 220). This in turn led to new hypotheses and
functional concepts of local RAS actions based on the
tissue-based synthesis of ANG II. It is not surprising that
the notion of tissue-based RAS with independent actions
was not received with great enthusiasm, but rather led to
significant controversies on the subject. Nevertheless, the
database on local RAS accumulated so far has by and
large been convincing and strengthened by two major
technical advances, namely, the use of molecular biology
and the availability of transgenic and knock-out models
with altered expression of RAS components (28, 31, 106,
370, 377, 534, 537, 696).
The genes for all components of the RAS have been
cloned, and gene expression studies could verify their
mRNA expression and regulation in many tissues, demonstrating the possibility of local ANG II synthesis. Overexpression of RAS genes in transgenic mice and rats as
well as the knock-out of these genes in mice have allowed
detailed studies on the function of local RAS (28, 31, 106,
370, 376, 534, 537, 696). It has also become increasingly
clear that these systems are not isolated entities but can
interact with the endocrine RAS as well as other peptide
systems (such as the endothelin system) on multiple levels (538, 582, 585, 614).
The early controversy on the novel concept of tissue
RAS has been based on the question of local synthesis
versus uptake from the circulation. A case in point represents the controversy between investigators after the
demonstration of renin expression in the heart (178, 415)
and those questioning local renin synthesis (751). This
controversy was based on the fact that detection of renin
mRNA in the heart could only be demonstrated inconsistently, leading to the suggestion that studies measuring
PHYSIOLOGY OF LOCAL RENIN-ANGIOTENSIN SYSTEMS
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ceptor is not only important for regulating the activity of
the system but also in the mediation of signal transduction processes, for example, in brain development and
cognitive function (568).
In the regulation of the RAS it is well established that
prorenin represents the inactive precursor of renin that
does not proteolytically self-activate like, for instance,
pepsinogen (689). This phenomenon has been attributed
to the prosegment with its 43 residues attached to the NH2
terminus of mature renin that prevents interaction with
angiotensinogen and thus cleavage of ANG I (40, 267,
650). While earlier in vitro studies have suggested that
prorenin can be activated by endopeptidases such as
trypsin and cathepsin B or by nonproteolytic mechanisms
such as by low pH (245, 465, 689), the mechanisms involved in prorenin activation in vivo and their physiological role are still not fully characterized (689). More recently, studies using specific antibodies designed from the
tertiary structure of prorenin have shown that there is an
essential region in the NH2-terminal region of prorenin,
which is responsible for the nonproteolytic form of activation (689). Suzuki et al. (689) have demonstrated two
key segments in this region termed the “gate” and “handle” regions. Subsequent studies (296) have further shown
that specific binding proteins, interacting with the “handle” region, are responsible for the nonproteolytic activation of prorenin through the induction of a conformational change. These findings shed new light on earlier
observations of an independent functional role of prorenin, suggesting that prorenin is a useful marker of diabetic
microvascular complications (143, 423, 481) and Wilm’s
tumor (379).
In the kidney it has been suggested that prorenin
uptake and intrarenal activation of the kidney RAS is
responsible for inducing renal damage and microvascular
changes (296). Interestingly, an earlier transgenic study
has come to similar conclusions using a reverse approach
(740). Overexpression of prorenin, subjected to site-directed mutagenesis at its proteolytic cleavage site in
transgenic rats, has led to high prorenin levels in the
plasma, but also to a severe renal phenotype characterized by severe nephrosclerosis in the absence of elevated
blood pressure (740). Now that the mechanisms of nonproteolytic activation of prorenin appear to be deciphered, this could finally solve the controversy of elevated prorenin levels and cardiovascular phenotypes not
only in the kidney but also in other organs such as the
heart (542). The proposed mechanism could be the basis
for the understanding of these phenomena and provide
new insights into the function of intracellular RAS and
their independence from the regulation of active renin in
the plasma. The identification of this receptor could play
an important role for the understanding of cellular effects
of prorenin/renin regulation of cell-specific ANG II formation. It is likely that this discovery could change our view
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binding protein on cardiac cells that is different from the
M6P receptor. The functional significance of prorenin
internalization in cardiomyocytes was shown in vitro and
in vivo, supporting the concept of an intracrine RAS in
these cells (488, 542).
It has also been suggested that proteins interacting
with renin could act as renin inhibitors in vivo, such as a
renin binding protein (RnBP) which was isolated from the
porcine kidney (698) and identified in porcine, rat, and
human tissues (693, 697, 698). Originally, RnBP was identified as a protein in the kidney that was capable of
binding renin in renal homogenates giving rise to a complex designated high-molecular-weight renin (698). Subsequently, RnBP was shown to be identical to the N-acylD-glucosamine 2-epimerase (437, 699). The gene encoding
RnBP has been mapped on chromosome X (697), and
chromosomal fine-mapping in the rat indicated that this
locus does not fall within a blood pressure quantitative
trait locus previously identified in rat models of hypertension (812). Moreover, knock-out of the gene encoding for
this protein in mice did not show any effects on RAS
activity or blood pressure (621), suggesting that RnBP is
of little functional significance in this context.
In contrast to these negative studies, a specific human renin receptor has been recently identified by expression cloning (490). The complementary DNA of this renin
receptor encodes a 350-amino acid protein with a single
transmembrane domain and no homology to any known
membrane protein (490). High expression levels are detected in the heart, brain, and placenta at the mRNA level,
while lower levels are observed in the kidney and liver
(488, 490).
This 45-kDa membrane protein binds both prorenin
and renin and shows a dual function (488). First, binding
of prorenin activates cellular effects that are independent
from ANG II generation by activating the mitogen-activated protein (MAP) kinases p(42)/p(44) and extracellular
signal-regulated kinases (ERK) 1/2 (488, 490). Second, this
receptor acts as a cofactor by increasing the efficiency of
ANG I generation on the cell surface by receptor-bound
prorenin and renin (488, 490). Additional studies showed
that the receptor is localized in the kidney in the mesangium and in the subendothelium of renal, uterine, and
cardiac blood vessels (488, 490). Nguyen and co-workers
(487, 489) demonstrated that renin can bind to this receptor in human mesangial cells in culture and that binding
induces hypertrophic effects and an increase of plasminogen activator inhibitor-1. Renin bound to this receptor
was neither internalized nor degraded (487, 489). The
gene encoding for this renin receptor, i.e., ATP6AP2,
maps to the X chromosome and was recently linked to
familial X-linked mental retardation and epilepsy syndrome (568). This clinical phenotype is caused by a
unique exonic splice enhancer mutation in ATP6AP2,
suggesting that the interaction between renin and its re-
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MARTIN PAUL, ALI POYAN MEHR, AND REINHOLD KREUTZ
of tissue RAS function by defining an independent functional role for prorenin and renin that are independent
from the effects of ANG II (and other peptides) generated
within the classical RAS cascade. Yet, the function, relevance, and tissue specificity of the renin receptor and
other potential pro(renin) binding mechanisms are still
poorly defined, and future research has to investigate
whether these sites function alone, together, or in combination with other mechanisms at the tissue level (87).
2. ANG-(1O7)
3. ACE and ACE2
Recently, a novel functional role of ACE involving
outside-in signaling has been identified by Fleming and
co-workers (208, 353–355). They demonstrated that ACE
inhibitor binding to ACE activates ACE-associated casein
kinase 2 (CK2)-mediated phosphorylation of ACE Ser1270 (355). Depending on initial phosphorylation, ACEassociated c-Jun NH2-terminal kinase (JNK) becomes activated, most likely via ACE-associated mitogen-activated
protein kinase kinase 7 (MKK7), leading to an accumulation of phosphorylated c-Jun in the nucleus and enhancement of the DNA-binding activity of activator protein-1
(AP-1, c-Jun dimer) (353). AP-1 activation influences endothelial gene expression, i.e., increases ACE as well as
cyclooxygenase-2 (COX-2) expression (354). Thus it was
shown that binding of an ACE inhibitor to ACE leads to
activation of signal events that are likely to affect the
expression of several proteins (208). The characterization
of the novel signaling pathway via ACE also suggests that
some of the beneficial effects of ACE inhibitors can be
attributed to the activation of a distinct ACE signaling
cascade rather than to the changes in ANG II and bradykinin levels (208).
ACE2 represents a zinc metalloprotease with carboxypeptidase activity that shares ⬃42% identity with the
catalytic site of somatic ACE and can be shed from cells
by cleavage NH2-terminal to the transmembrane domain
(169, 713). ACE2 is involved in the generation of alternaPhysiol Rev • VOL
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Alternative cleavage products of ANG I have been
suggested as functional peptides in the RAS (200, 201, 595,
596). The most extensively studied of these is
ANG-(1O7), which is generated by the action of several
ACE-independent enzymes from ANG I (200). Some of
these enzymes such as neprylisin are also involved in the
metabolism of atrial natriuretic factors and bradykinin,
and ACE has been shown to be active in metabolism and
breakdown of ANG-(1O7), suggesting a complex interaction between different cardiovascular peptide systems
(769). ANG-(1O7) has multiple actions that are mostly
counteracting those described for ANG II (201, 310, 420,
596).
tive angiotensin peptides in particular by the conversion
of ANG II to ANG-(1O7) and ANG I to ANG-(1O9) (169,
741). Thus, while ACE generates ANG II from ANG I
through cleavage of the COOH-terminal dipeptide HisLeu, ACE2 catalyzes the conversion of ANG II into ANG(1O7) by removing the COOH-terminal amino acid phenylalanine. In addition, ACE2 can cleave the COOH-terminal residue of the decapeptide ANG I, thus generating
the nonapeptide ANG-(1O9), which may be subsequently
converted to ANG-(1O7) by ACE. ACE2 can also cleave
des-Arg(9)-bradykinin but does not hydrolyze bradykinin
and is insensitive to ACE inhibitors (169, 713, 741). The
fact that ACE2 generates the vasodilator ANG-(1O7) can
be viewed as a further counterbalancing tissue-specific
mechanism within the activated RAS.
The expression of ACE2 is (in comparison with
ACE) relatively restricted to cardiac blood vessels and
tubular epithelia of the kidneys, which together with its
differential enzyme activity might suggest a distinctive
physiological function blood pressure and volume regulation (128, 713). A recent study (119) has mapped
ACE2 to a region on the X chromosome that is thought
to be involved in the genetic modulation of hypertension (271, 794, 812). However, a potential role of ACE2
for genetic hypertension appears questionable since the
reported expression analysis of ACE2 in hypertensive
rat strains (119) was at variance with the allelic effects
at the blood pressure loci observed in mapping analysis
with these strains (271, 794, 812). Crackower et al.
(119) performed a number of knock-out studies in mice
and Drosophila, and while there were only modest
effects on blood pressure in mice, the genetic manipulation resulted in severe changes in cardiac contractility, combined with increases of cardiac ANG II levels
and the induction of gene pathways mediating the response to hypoxia (119). Therefore, it has been suggested that ACE2 is important as a regulator of heart
function and development. Further expression studies
of ACE2 on the mRNA and protein level extended the
spectrum of organs in which this enzyme is expressed
(251, 251, 257) and particularly demonstrated that
ACE2 is abundantly present in humans in the epithelia
of the lung and small intestine (251). However, taken
together, no clear picture of the tissue distribution of
ACE2 expression and the physiological role assigned to
ACE2 has been yet obtained. Interestingly, work in cell
lines suggested that ACE2 is the functional receptor for
coronavirus associated with the acute respiratory syndrome, i.e., SARS-CoV (408, 789). The functional role
for ACE2 for SARS-CoV replication in vivo was subsequently confirmed in mice (364). Additional studies
could demonstrate that ACE2 protects against lung
injury caused by SARS-CoV and other agents (301, 364).
PHYSIOLOGY OF LOCAL RENIN-ANGIOTENSIN SYSTEMS
4. N-acetyl-Ser-Asp-Lys-Pro
5. Chymase
An ANG II-forming serine protease termed human
heart chymase has been postulated as an activator in an
alternative pathway of ANG II formation in the heart (728,
730). It is not affected by ACE inhibition and has been
suggested as relevant for alternative pathways of ANG II
generation (728, 730, 781). Although several other alternative enzymes involved in ANG II formation had been
described previously such as cathepsins and tonin, chymase deserves special attention due to its high substrate
specificity. The enzyme is also expressed in the vascular
wall, where it has been suggested as a possible player in
ANG II-mediated arteriosclerosis (20). Although its ultimate relevance for the cardiac RAS remains to be determined, since its cellular localization is largely restricted to
mast cells (418, 728), experimental studies with selective
chymase inhibitors in animal models of heart diseases
have thus far generated promising results (167, 700).
6. Angiotensin receptors
The actions of ANG II are mediated predominantly by
two seven transmembrane domain receptors termed AT1
and AT2 showing a complex pattern of regulation and
function (142, 306, 336, 462, 604, 639, 681, 712, 724, 725,
785). In rat and mouse, two AT1 subtypes have been
cloned and characterized; they are termed AT1A and AT1B
(302). The AT1 and AT2 subtypes show similar properties
of ANG II binding but different genomic structure and
localization as well as tissue-specific expression and regulation (142). Whereas most of the well-known actions of
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ANG II such as vasoconstriction and aldosterone release
are mediated by the AT1 receptor, the AT2 receptor has
been considered to be more of an enigma (403, 724). It
appears to play an important functional role in prenatal
development, and in the adult, AT2-mediated actions have
been shown to counteract AT1 effects such as cell proliferation in vitro (681) and in vivo (462). Increasing evidence supports a role of AT2 particularly in the regulation
of growth, differentiation, and regeneration of neuronal
tissue (676). The existence of an additional ANG receptor
termed AT4 has been postulated, which is interacting with
a truncated ANG peptide, ANG IV or ANG-(3O8) (66, 89,
691, 785). Thus the AT4 receptor was originally defined as
the specific, high-affinity binding site for the hexapeptide
ANG IV. Subsequently, the peptide LVV-hemorphin 7 was
also demonstrated to be a bioactive ligand of the AT4
receptor (453). The AT4 binding site has been found in
heart, vascular smooth muscle, kidney, colon, adrenal
gland, prostate, and many brain regions in processing
sensory and motor function (66, 89, 255, 691, 785).
Two additional novel mechanisms of ANG receptor
binding leading to contrasting effects have been recently
demonstrated (1, 140, 141, 756). First, AbdAlla et al. (1)
reported that the AT2 receptor can directly bind to the
AT1 receptor and thereby antagonizes the function of AT1.
It was shown that heterodimerization between both receptors led to inhibition of AT1 signaling that was independent of AT2 receptor activation (1). Second, activation
of AT1 receptor by autoantibodies in women with preeclampsia was demonstrated (756). These stimulatory autoantibodies are directed against the second extracellular
AT1 receptor loop and are capable of inducing PKC-mediated effects in vascular smooth muscle cells (756). Although both mechanisms have not been proven with certainty and confirmed by independent groups, they opened
new arenas for future research regarding ANG receptor
activation and inhibition.
6. Mas
The Mas protooncogene is characterized as a G protein-coupled receptor originally described as a factor involved in tumorigenesis. It has been suggested that Mas is
a functional ANG receptor (311), a hypothesis which has
been challenged since binding of ANG II to cells expressing Mas could not be shown, suggesting that it is only
indirectly involved in ANG II signal transduction. Experiments on Mas knockout mice have indeed shown a functional interaction between Mas and the AT1 receptor
(750). This interaction may be attributable to heterooligomerization between Mas and the AT1 receptor and leading to inhibition of ANG II effects mediated by AT1 (359).
It remains to be determined, however, whether the proposed effects mediated by ANG-(1O7) or other ANG pep-
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It is well-known that ACE is acting on several substrates such as ANG I and bradykinin. One of these,
N-acetyl-Ser-Asp-Lys-Pro (Ac-SDKP), is a hematopoetic
factor that is a natural substrate for the NH2-terminal
domain of ACE (573). The breakdown of Ac-SDKP can be
blocked by ACE inhibitor treatment resulting in an increase of its plasma levels, and it has been suggested that
measurement of Ac-SDKP could be a marker for the clinical efficiency of ACE inhibition (25). In the hematopoetic
system, Ac-SDKP acts on the cell cycle and prevents the
activation of pluripotent stem cells (26), and levels of
Ac-SDKP have recently been associated with anemia in
heart failure patients treated with ACE inhibitors (734).
Although its relevance for cardiovascular regulation still
remains unclear, accumulating data indeed support a
functional role of Ac-SDKP (554, 555, 569, 761, 800).These
functions might include the stimulation of angiogenesis
(761) and particularly antifibrotic effects that could point
to possible effects in repair and remodeling processes in
the cardiovascular system (554, 555, 569, 761, 800) and
kidney (88, 646, 744).
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MARTIN PAUL, ALI POYAN MEHR, AND REINHOLD KREUTZ
tides via Mas could indeed be of functional relevance in
vivo (597).
II. LOCALIZATION AND FUNCTIONAL ASPECTS
Whereas many previous studies on localization and
function of tissue or local RAS have focused on their
pathophysiological relevance, many new aspects of a
physiological role for these systems have been uncovered.
Cloning of all relevant RAS genes as well as the establishment of transgenic and knock-out models have enhanced
this knowledge significantly. It appears likely that local
and systemic actions of the RAS have to be integrated in
a concerted action of ANG-mediated effects. In addition,
an independent function of local RAS (for example, in the
brain where the RAS components are also expressed in
regions inside the blood-brain barrier) has been postulated. The most significant contribution of the locally
acting systems is their function at the cellular level. In this
context, paracrine and autocrine effects appear of particular importance, which mediate cell specific effects on
cell growth, proliferation, and metabolism. There have
also been some suggestions of intracellular or intracrine
RAS actions (175) mediated by ANG binding in the cell
nucleus (704). Nevertheless, this intracellular concept of
ANG II synthesis and function awaits final confirmation.
The purpose of this review is to integrate aspects of
localization of local RAS components with function and
will focus predominantly on the physiological rather than
pathophysiological implications of these findings. In some
instances, pathophysiological concepts will be used to
enhance understanding of their physiological basis. We do
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not discuss the RAS in kidney and adrenal gland as these
have been extensively reviewed elsewhere (28, 59, 76,
259, 318, 343, 373, 376, 401, 425, 450, 473, 627, 652), and we
rather focus on local RAS in other organs that are not
typically associated with ANG formation.
A. Heart
The existence and function of a specific cardiac RAS
has been a matter of debate since it has been difficult to
differentiate the effects of intracardiac ANG II generation
from actions by plasma-borne ANG II. Nevertheless, it has
become quite clear that cardiac actions of drugs inhibiting
ANG II actions such as ACE inhibitors and ANG II receptor blockers are in part explained by local effects at the
cellular level, for example, on cardiac remodeling. The
predominant physiological role of the cardiac RAS appears to be the maintenance of an appropriate cellular
milieu balancing stimuli inducing and inhibiting cell
growth and proliferation as well as mediating adaptive
responses to myocardial stress, for example, after myocyte stretch. A schematic representation of cardiac ANG
pathways is shown in Figure 1.
1. Renin
The existence and relevance of cardiac renin expression has been a matter of controversial debates, although
some investigators have been able to detect renin mRNA
in the heart by Northern blotting (174), solution hybridization assays (531), and RT-PCR (532) in various species.
Renin mRNA expression in all of these studies, however,
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FIG. 1. The renin-angiotensin system
(RAS) in the heart. Renin and angiotensinogen (AOGEN) are mostly taken
up from the plasma or formed locally.
Mast cell production of human heart chymase may present an alternative pathway. ANG II synthesis occurs extracellularly and acts on cell-specific receptors
on different cell types such as cardiomyocytes and fibroblasts.
PHYSIOLOGY OF LOCAL RENIN-ANGIOTENSIN SYSTEMS
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circulation (134) either due to nonspecific uptake (diffusion) into the cellular interstitium (144, 315, 542) or
through the actions of specific functional binding sites or
receptor for prorenin and renin (87, 488, 490, 541). The
M6P receptor has been shown to bind prorenin and renin
cells on cardiomyocytes (601, 603). Hypertrophy of isolated neonatal cardiomyocytes in culture and increase in
protein synthesis were only detected during coincubation
of prorenin with angiotensinogen, while prorenin binding
alone had no effect (603). The effects of prorenin plus
angiotensinogen were comparable to those of 100 nM
ANG II, although the ANG II levels in the medium during
exposure of the cells to prorenin plus angiotensinogen
were ⬍1 nM. This suggests that cardiac ANG II generation
by circulating renin occurs predominantly on the cell
surface (315, 603). In addition, the newly identified prorenin and renin receptor that is capable of activating
signal transduction via MAP and ERK kinases independently from ANG II generation shows high expression
levels in the heart (488, 490). Taken together, these findings support the concept that the physiological role of the
tissue RAS in the heart depends on the assembly of prorenin and renin binding receptors including M6P and ANG
receptors (488, 603). This favorable microenvironment
would allow maximal efficiency of local ANG II generation, i.e., immediate binding of ANG II to its receptors
with minimal loss into the extracellular space (315, 488,
603).
A recent study could show that unglycosylated renin
is rapidly taken up by cardiomyocytes by a mechanism
that is independent from the M6P receptor and that transgenic rats with overexpression of the mouse Ren-2 gene
(which have high prorenin levels in the plasma) exhibit
strongly enhanced intracellular levels of unglycosylated
renin in their hearts (542).
2. ACE
The existence of local ACE production in the heart is,
in contrast to the renin, no matter of controversy. Cardiac
ACE mRNA can be easily detected by a number of methods in rat (277, 362, 626) and human hearts (532). ACE
activity is also readily detectable, for example, by autoradiography (796) or enzymatic assay (278, 362, 726). Immunohistochemistry has been used to localize the predominant source of ACE expression in cardiac blood
vessels and the endocardium (190), whereas mRNA studies on cultured cardiac cells also found ACE expression in
cardiomyocytes (536). These studies have been confirmed
by expression studies showing that ACE is present in
viable human cardiomyocytes after myocardial infarction
(284). ACE2 expression has also been demonstrated in
the heart in both animals (119, 713) and humans (67, 238).
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was rather low, and very high amounts of mRNA or total
RNA had to be used to bring the renin signal to the level
of detection. Other investigators challenged these findings
and were unable to find proof for local mRNA expression
in the literature (751), claiming that the measurement of
cardiac renin mRNA was based on contamination problems and artifacts. This was supported by findings that
cultured cardiomyocytes or fibroblasts did not synthesize
renin. Ultimate proof of the presence of local renin synthesis in the heart was to be expected by transgenic
overexpression using the native renin promoter. Transgenic mice carrying a genomic human renin construct
showed no cardiac renin expression (798), whereas transgenic rats carrying a genomic construct of the mouse
Ren-2 gene under control of its own promoter expressed
high levels of renin mRNA in the heart (549). This suggests that at least in some species, the heart is a site of
extrarenal renin production. Other authors have suggested that, whereas renin is not synthesized in the heart
under physiological conditions, renin gene expression
may be turned on in pathophysiological situations (147).
It is interesting to note in this context that an additional
truncated renin mRNA has been described in heart tissue
which lacks the prefragment of preprorenin and results in
the formation of a truncated prorenin protein termed
exon 1A renin (103, 541). The initial characterization of
this isoform in rat adrenocortical cells revealed that this
alternative transcript encodes for a truncated prorenin
that is imported into mitochondria (104). Subsequent
studies demonstrated the expression of this truncated
isoform in the rat heart and suggested that only this
alternative renin transcript but not the full-length isoform
is expressed in the rat heart (103, 541, 542). This conclusion was based on studies in which renin expression was
analyzed by a sensitive nested RT-PCR method allowing
the differentiation between the full-length transcript coding for preprorenin and the transcript coding for the
truncated intracellular isoform (103, 541, 542). While the
latter was detected in various rat tissues in parallel with
the full-length mRNA, the exon 1A renin was the only
transcript of the renin gene expressed in the heart (103,
541, 542). Moreover, it was shown that in disease states
such as cardiac hypertrophy or myocardial infarction,
there is no expression of the mRNA coding for the fulllength preprorenin but exclusively the exon 1A renin
transcript is increased (103, 542). The recent findings on
the differential regulation of preprorenin, i.e., the classical full-length renin, and exon 1A truncated renin in the
heart might explain some of the previous controversies
and discrepancies in the literature regarding renin expression in the heart, since investigators were unable to differentiate between the two isoforms before the identification of exon 1A renin (541).
Less controversial is the evidence for the presence of
renin protein in the heart attributed to uptake from the
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MARTIN PAUL, ALI POYAN MEHR, AND REINHOLD KREUTZ
3. Chymase
4. Angiotensinogen, ANG I, and ANG II
The detection of angiotensinogen mRNA in the heart
has been described for mouse (174), rat (268, 417), dog
(382), and human (532). Although the cardiac mRNA levels of angiotensinogen are more readily detectable than
those of renin, they are low compared with those found in
liver, the major source of angiotensinogen production
(174). Arguments against local mRNA synthesis of cardiac
angiotensinogen stem from experiments in isolated perfused rat hearts where there was no endogenous angiotensinogen release detectable (144). These authors concluded that the major percentage of cardiac angiotensinogen is due to plasma uptake and presented evidence that
the protein is rapidly taken up into the cardiac interstitium when added to the perfusate.
ANG peptides have been detected in the heart (132,
416) at concentrations higher than those found in the
plasma compartment. Although this could be seen as an
indicator of cardiac synthesis, the issue of cardiac uptake
and local storage of ANG II should be considered. Alternatively, renin and angiotensinogen taken up from the
circulation could be interacting with local ACE to lead to
intracardiac ANG II formation. To address this question,
van Kats et al. (736) used infusions of radiolabeled ANG I
and ANG II peptides in pigs and measured plasma and
Physiol Rev • VOL
5. Angiotensin receptors
Both the AT1 and the AT2 receptors are expressed in
the heart where they appear to be localized on cardiomyocytes (28, 55, 577, 590, 729). On cardiac fibroblasts, the
receptor population appears to be dependent from the
presence or absence of cardiac disease. Normal fibroblasts express AT1 only but can recruit the AT2 receptor
under certain pathological conditions (118, 510, 635). The
function of the two ANG receptors in the heart has been
seen in perspective of a “Ying-Yang” principle, meaning
that the AT1 is a stimulator of hypertrophy and proliferation of cardiac cells, whereas AT2 is mediating the opposite effects (773). Transgenic and knock-out studies in
mice, however, have not supported this concept in the
heart, since knockout of the AT2 receptor in mice has
suggested that the receptor is also needed for the mediation of hypertrophic stimuli (705). Moreover, conflicting
experimental data obtained more recently in animal studies using either selective AT2 antagonists or genetically
modified mice have raised some concern regarding the
beneficial role of AT2 stimulation in both the heart and
vasculature in disease states (403).
6. Function
A) INOTROPIC EFFECTS. Koch-Weser (351) first suggested
that ANG II acts as an inotropic agent (351) but only at
“supraphysiological” concentrations. The effect could at
least in part be indirect by ANG II acting, for example, on
the sympathetic nervous system (352). Nevertheless, direct effects by ANG II have been verified (148), which are
thought to be mediated by intracellular calcium influx and
changes of the plateau phase of the cardiac action potential. In vitro studies in human preparations carried out
physiological conditions in right atrial and right and left
ventricular myocardial preparations of patients with a
variety of cardiac diseases suggested that ANG II exerts
positive inotropic effects only in atrial preparations (286).
However, transgenic overexpression of the human AT1
receptor on cardiac myocytes in a transgenic rat model
has supported the early findings since transgenic AT1
upregulation led to an enhanced intracellular calcium
response after ANG II stimulation (280).
B) HYPERTROPHIC EFFECTS. ANG II mediates myocyte hypertrophy due to activation of the AT1 receptor as an
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Human heart chymase activates ANG I to ANG II but
is not inhibited by ACE inhibitors and could act as an
activator for alternative pathways of ANG II formation.
Using whole heart homogenates, Urata et al. (729) described that up to 80% of ANG II forming activity in the
heart was due to chymase, while only 11% was based on
ACE activity, suggesting an increased importance of the
chymase pathway in the human heart. When comparing
studies in humans and animals, it is important to consider
the important species differences in the pathways of intracardiac ANG II generation (30). In this regard, chymase
predominates over ACE activity in human heart, accounting for considerably higher total ANG II formation in
human heart compared with dog, rat, rabbit, and mouse
hearts (30). The ultimate functional importance of a chymase-dependent pathway of ANG II formation in the heart
remains questionable due to a number of factors: 1) clinically, ACE inhibitors are extremely efficient in the treatment of cardiac disease; 2) under experimental conditions, most of the ANG II generated by intact cardiac
blood vessels can be blocked by ACE inhibitors; and 3)
the expression of human heart chymase is highly compartmentalized and mostly restricted to mast cells (728).
Nevertheless, ANG II-generating pathways in the heart
that are independent from ACE might be particularly
important in disease states such as cardiac hypertrophy
(407) and heart failure (781).
tissue levels of endogenous as well as the radiolabeled
peptides. The results of this study indicated that ⬎90% of
cardiac ANG I is synthesized locally in the heart and that
⬎75% of cardiac ANG II is synthesized locally, most of it
using local ANG I generation as a basis. These findings
clearly show the local synthesis of ANG peptides in the
heart as a relevant mechanism and point out that the
concept of a cardiac RAS is not dependent on the local
synthesis of angiotensinogen and renin.
PHYSIOLOGY OF LOCAL RENIN-ANGIOTENSIN SYSTEMS
Physiol Rev • VOL
with wild-type mice. Cardiac hypertrophy in transgenic
mice is also associated with SERCA2 activity and reduced
Ca2⫹ transport. Moreover, systolic function was also impaired as evidenced by impaired contractility in isolated
cardiomyocytes (168). Equivocal results have been obtained with regard to the role of the AT2 receptor in
cardiac hypertrophy (403). While the AT2 receptor has
been initially associated with antihypertrophic effects
(403), some studies in AT2-deficient mice indicated that
AT2 has a significant effect on cardiac hypertrophy induced by aortic banding (635) or ANG II infusion (297).
C) MECHANICAL STRETCH. Several lines of evidence indicate
that ANG II pathways can be defined as a “rapid response
system” for mechanical stretch in the heart, which may be
involved in the mediation of cardiac hypertrophy (100).
Stretch can induce ANG II release into the media of
cultured cardiomyocytes in vitro (587) and in vivo (391),
and virtually the expression of all gene transcripts of the
RAS can be stimulated by stretch (432). Overload of the
left ventricle, which represents a situation associated
with chronic stretch of cardiomyocytes, results in a similar activation of the cardiac RAS (29, 626). The intracellular pathways activated by the induction of the cardiac
RAS and local ANG II production in cultured neonatal
cardiomyocytes are blocked by AT1 receptor antagonism
(357). The signaling is mediated by p53 as well as by the
JAK/STAT pathway (391). Whereas initially it was thought
that these effects are mediated entirely through the AT1
receptor, recent AT2 knock-out studies in mice have revealed that the AT2 receptor is also involved in mediating
these changes (635).
D) REMODELING. Proliferative stimuli by cardiac ANG II
are probably most relevant for the fibroblast portion of
cardiac cell population as has been shown by Schelling
and Ganten (606, 608). Similar mechanisms have been
described during cardiac remodeling where fibroblast
proliferation has been shown as a cellular indicator of
pathological changes. Local ACE formation appears to
play an important role in this process, since previous
studies in a rat heart failure model induced by experimental myocardial infarction (which goes along with increased fibrosis) have demonstrated an activation of cardiac ACE activity and mRNA, whereas plasma ACE activity was not changed (277).
In rat hearts, Sun and Weber (687) have shown that at
weeks 1 and 4 after myocardial infarction myofibroblasts
were the predominant cell expressing high-density ANG II
receptors at this site, while fibroblasts, macrophages, and
vessels demonstrated low-density ANG II receptor binding. After myocardial infarction in rats treated with the
AT1 antagonist losartan, a significant reduction in collagen volume fraction at remote sites of the infarction was
found compared with untreated animals (139).
Since either AT1 blockade or ACE inhibition is not
associated with any normalization of elevated collagen
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adaptive response to increased myocardial stress. While
hypertrophy of cardiomyocytes acts initially as a compensatory mechanism to preserve cardiac function, it becomes a major risk factor for congestive heart failure and
sudden cardiac death and overall mortality (172). In vitro
studies have demonstrated this effect in cultured cardiomyocytes (738), and it has been suggested that this effect
is secondary to the release of other growth factors such as
endothelin-1 and transforming growth factor (TGF)-␤
(239). Left ventricular hypertrophy due to enhanced ANG
II production in the heart has also been described in
transgenic rat models with overexpression of RAS components such as mouse renin (549), the human AT1 receptor (279, 280), human ACE (555, 711), and double transgenic rats expressing human renin and human angiotensinogen (470). In some of these models it has been
clearly shown that the ANG II effects occur independently
from its effects on blood pressure, suggesting a functional
role of the local cardiac RAS in mediating these changes.
Hypertrophic changes induced by ANG II are mediated by
several distinct intracellular pathways such as the activation of tyrosine kinase and RhoA cascades which include
activation of MAP kinase and JAK/STAT pathways (142,
435, 613, 725). An important maladaptation in left ventricular hypertrophy relates to diastolic dysfunction that results from functional changes such as impaired diastolic
calcium handling and/or structural changes such as cardiac fibrosis (101, 586, 629). Studies in rats with experimental left ventricular hypertrophy indicated that locally
generated ANG II may disturb relaxation, i.e., diastolic
function, of the heart (629). This notion was supported by
subsequent studies in transgenic rats with activated tissue
RAS showing significant impairment of diastolic relaxation (585, 586). Moreover, diastolic function could be
restored by treatment with a non-blood pressure-lowering
dose of an AT1 receptor antagonist (586). Functional analysis of left ventricular dysfunction in this setting indicated
that the impairment of diastolic dysfunction was attributable to impaired diastolic sarcoplasmic reticulum calcium
pump (SERCA2) activity (586). A similar effect could also
be induced in the same rat model by treatment with a
selective endothelin A receptor antagonist, demonstrating
the activation of the endothelin system in rats with activated tissue RAS and its functional consequence in the
heart (585). Chronically, activation of the cardiac RAS
may not only lead to cardiac hypertrophy and diastolic
function but also to progressive systolic dysfunction, cardiac enlargement, and heart failure. The independent role
of cardiac RAS activation for these consequences has
been recently demonstrated in transgenic TG1306/1R
mice that develop ANG II-mediated cardiac hypertrophy
in absence of elevated blood pressure (168). A long-term
follow up study in these mice demonstrated that transgenic animals develop dilated cardiomyopathy with aging
and exhibit a significant increase in mortality compared
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MARTIN PAUL, ALI POYAN MEHR, AND REINHOLD KREUTZ
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heart surgery, patients with a history of paroxysmal or
persistent atrial fibrillation showed increased interstitial
fibrosis and threefold higher ACE tissue levels compared
with patients in sinus rhythm (233), while the densities for
the AT1 receptor was decreased and increased for AT2
receptors (231). Most importantly, evidence obtained
from recent pharmacological intervention studies has
pointed to a new concept in which inhibition of the RAS
by ACE inhibitors or AT1 antagonists may induce specific
benefits in patients with atrial fibrillation (232, 265, 649).
E) APOPTOSIS. Whereas earlier studies carried out in
PC-12 cells (a rat pheochromocytoma cell line) have suggested that programmed cell death is mediated by the AT2
receptor (797), it is generally accepted that apoptosis of
cardiac myocytes is mediated via the AT1 receptor (99).
The process is thought to be involved in cardiac remodeling, for example, after myocardial infarction (19), hypertensive cardiomyopathy (163), and diabetic cardiomyopathy (206). It can be effectively blocked by AT1 antagonists (160), which suggests that the beneficial effects of
RAS blockade in heart failure could be due in part to this
intracardiac mechanism.
B. Vasculature
The vascular wall is the effector organ for the hormonal or plasma RAS where AT1 receptors localized on
vascular smooth muscle cells mediate vasoconstriction.
The concept of a vascular RAS was generated when it
became evident that ANG II can differentially affect
growth properties of vascular cells and that RAS components can be formed intracellularly in the vasculature.
1. Renin
Whereas some studies have not found renin activity
in blood vessels (210), others have found renin mRNA
expression in conductance and resistance vessels of human (532) and rat (594). Nevertheless, renin mRNA has
been difficult to detect due to the small sample size which
very often required pooling of samples and the use of
more sensitive assays such as RNase protection assays as
well as RT-PCR. This has led to a similar controversy as
that concerning renin in the heart, and it has been proposed that local renin synthesis is negligible if at all
present in the vasculature (751). Although this may be
true under physiological circumstances, it is possible that
local renin production may be turned on in disease states.
In this context, vascular renin induction has been demonstrated in the rat neointima model (309).
In addition to local synthesis, renin uptake via unspecified binding sites on endothelial cells or specific
prorenin/renin receptors (87, 315, 488, 490) has been suggested as a relevant mechanism. The M6P receptor was
shown to bind renin and prorenin on human endothelial
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mRNA after rat myocardial infarction, Dixon et al. (165)
suggested that the reduction of cardiac fibrosis mediated
by ACE inhibition and losartan treatment may reside at
the posttranslational level in cardiac collagen metabolism. The RAS has apparently multiple targets involved in
cardiac remodeling. Tan et al. (702) measured the cardiotoxic effects of ANG II in rats. The authors have shown
that pathophysiological levels of endogenous as well as
nonhypertensive low doses of exogenous ANG II produced multifocal antimyosin labeling of cardiac myocytes
and myocytolysis, increased DNA synthesis rate and fibroblast proliferation. Both myocyte injury and fibroblast
proliferation were prevented with captopril (702).
The mechanisms leading to ANG II-induced fibrosis
are thought to be at least partially mediated through
growth factor pathways induced by AT1 receptor activation (548, 686). In this context, TGF-␤ has been implicated
as a candidate. Studies on transgenic rats expressing the
mouse Ren-2 gene have shown that inhibition of TGF-␤
synthesis by the specific growth factor inhibitor tranilast
did not affect blood pressure but resulted in a significant
alleviation of interstitial cardiac fibrosis seen in this
model, which was also associated with longer survival of
treated transgenic animals (548).
Another mediator, osteopontin, which is involved in
the vascular smooth muscle cell remodeling process, is
increased at mRNA and protein levels after addition of
ANG II to rat cardiac fibroblasts (24, 506). This effect is
blocked by the AT1 receptor blocker losartan. This suggests that osteopontin is a potentially important mediator
of ANG II regulation of cardiac fibroblast behavior in the
cardiac remodeling process. Indeed, osteopontin mRNA
is elevated in transgenic rats, the mouse Ren-2 gene already in the prehypertensive phase, which suggests that it
contributes directly to the contractile dysfunction seen in
this model and is blood pressure independent (584).
Yet another mediator in the inhibition of cardiac
fibroblast proliferation appears to be the recently described alternative substrate of ACE, AC-SDKP, a hematopoetic stem cell regulator, is hydrolyzed by the NH2terminal active site of ACE. It has been demonstrated that
the administration of ACE inhibitors stimulates AC-SDKP
plasma levels over fivefold (25), which could be a plasma
marker for efficient ACE inhibition. Recently, it has also
been demonstrated that AC-SDKP inhibits also fibroblast
proliferation in a dose-dependent manner (554), suggesting that the alternative substrate could be the mediator of
antiproliferative effects on fibroblasts in cardiac remodeling seen after ACE inhibition. This fascinating hypothesis, however, awaits final confirmation.
In addition to the structural abnormalities related to
activation of the cardiac RAS, increased activity of the
system has also been linked to changes in the electrical
physiology that lead to arrhythmias both in the ventricle
and atria (146, 266). Indeed, in human patients undergoing
PHYSIOLOGY OF LOCAL RENIN-ANGIOTENSIN SYSTEMS
2. ACE
In the vascular wall, ACE is readily detectable, where
it is localized predominantly on the surface of endothelial
cells (190, 811). There are controversial data regarding the
distribution of ACE expression in different layers of vascular wall. Wilson et al. (776) found a predominant labeling in the endothelium and adventitia. This finding was
confirmed by Rogerson et al. (578) in human, dog, rabbit,
and sheep arteries. Arnal et al. (22) have shown high ACE
mRNA and protein expression as well as immunoreactivity in the media of rat aorta where the expression level is
almost as high as in the endothelium, while expression is
low in the adventitia. Several reports have indicated that
vascular smooth muscle cells, which do not appear to
express ACE, can do so in certain pathophysiological
situations such as neointima formation (197). Low
amounts of ACE have also been detected in the adventitia
of blood vessels (578).
ACE2 mRNA expression is ubiquitously found in arterial and venous endothelial cells and arterial smooth
muscle cells in all organs studied by Hamming et al. (251).
An important role for ACE and ACE2 in the pulmonary
vasculature and epithelial cells during injury and/or SARS
virus infection has been recently supported (301, 364,
491). However, further studies are required to delineate
the cell types responsible for RAS component expression
in the lung and to identify the physiological role of the
pulmonary RAS (436). This will also provide a better
understanding of the activated RAS, and particularly the
Physiol Rev • VOL
potential protective effect of ACE2 in lung disease (436,
491).
3. Angiotensinogen, ANG I, and ANG II
The substrate of the RAS cascade has been detected
in blood vessels at the mRNA level (74, 268). In situ
hybridization studies showed that it is abundantly expressed in periadventitial fat cells (73, 84). This led to the
suggestion that angiotensinogen is secreted by these cells
and diffuses through the vascular wall where it gets in
contact with vascular renin.
4. Angiotensin receptors
Both AT1 and AT2 receptors were identified in the
vasculature (54, 475). Initially the function of these receptors was investigated on cultured primary vascular cells.
Vascular smooth muscle cells in culture express only the
AT1 receptor, whereas cultured endothelial cells expressed both AT1 and AT2 (681). ANG II stimulated
growth of vascular smooth muscle cells, while the peptide
inhibited the growth of quiescent coronary endothelial
cells in response to stimulation by basic fibroblast growth
factor (681). In the presence of an AT2 receptor antagonist, this effect was abolished, suggesting a growth-inhibiting role of AT2 (681). Later, this interesting concept was
also reproduced in an in vivo experiment of AT2 gene
transfer in balloon-injured rat carotid arteries, which led
to a reduction of neointima formation, an effect which
was neutralized by an AT2 antagonist (461). The distribution of the AT2 receptor in the vascular wall is nevertheless a matter of debate (39). Overall, functional studies in
isolated arteries from both animals and humans accumulated a large body of evidence that the endothelium is the
most important side for AT2 receptor expression (38, 39,
46, 234, 254, 622). In addition, since AT2 may form heterodimers with AT1 receptors (1), this would require a
colocalization of both receptors and thus points to the
additional expression of AT2 expression on vascular
smooth muscle cells in the vascular wall (39).
5. Function
A) VASCULAR TONE AND ENDOTHELIAL FUNCTION. The tissue RAS
contributes to the maintenance of cardiovascular homeostasis by the dual impact on vessel function mediated
through the opposing effects of its two receptors. In in
vivo studies, i.e., in the whole body situation, it is not
possible to clearly dissect between effects mediated by
ANG II generated in the plasma and effects attributable to
ANG II generated within the vessel wall. Nevertheless,
earlier studies documented the potential of ANG II generation within the vasculature. The local generation of
ANG II in the vasculature has been demonstrated in isolated perfused rat hindquarters (272). Hilgers et al. (272)
reported that ANG I can be converted to ANG II by ⬃50%
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cells (5), and studies in endothelial cells indicated that
uptake of prorenin by M6P may represent a clearance
mechanism for prorenin (733). This could in fact provide
a protective mechanism during activation of the RAS
either systemically or at the tissue level. The potential
importance of this mechanisms was shown by generation
of a transgenic rat model that directed high prorenin
expression and release into the plasma from the liver
(740). This led to dramatic increases in plasma prorenin
that were up to 400-fold. Interestingly, these animals did
not have higher blood pressures than controls, yet developed severe vascular lesions, suggesting that prorenin is
taken up from the circulation and stimulating the intracellular RAS leading to pathological trophic effects (740).
Moreover, in humans, increases in circulating prorenin
levels have been associated with disease states such as
diabetic microvascular complications (143, 423, 481). It
thus appears of interest for further studies to evaluate the
functional role of prorenin clearance and elimination in
the endothelium by M6P or other mechanisms. These
effects have to be balanced against mechanisms such as
binding by the prorenin/renin receptor (490) or nonproteolytic activation of prorenin (296, 689) that would lead
to the activation of the RAS (87, 315, 488, 490).
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MARTIN PAUL, ALI POYAN MEHR, AND REINHOLD KREUTZ
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dative stress via the AT1 receptor (71, 253, 623). In this
regard, ANG II plays an important role in modulating the
balance between NO and ROS in the endothelium and
thereby maintaining homeostasis of the vascular wall.
Oxidative stress has been shown to play a critical role in
the development of endothelial dysfunction and hypertension and atherosclerosis (4, 253, 623). Nevertheless, the
relative contribution of redox-independent hemodynamic
mechanisms and oxidative stress in maintaining vascular
function and their modulation by ANG II via AT1 and AT2
receptors needs further in-depth analysis.
6. Tissue remodeling
In addition to the well-established long-term effects
of the RAS on vascular remodeling that are mediated by
proliferative effects on vascular smooth muscle cells and
fibroblast (9, 75, 223, 227, 607), the production of ROS by
NAD(P)H oxidase in response to ANG II has been demonstrated as an important mechanism linking activation
of the RAS to events such as inflammation, atherosclerosis, hypertrophy, remodeling, and angiogenesis (71, 253,
623).
The production of ROS by NAD(P)H oxidase in response to ANG II stimulation in endothelial and vascular
smooth muscle cells activates signal pathways such as
MAP kinases, tyrosine kinases, and transcription factors
that lead to theses events (71, 240, 253, 623). In the ANG
II/AT1-driven processes leading to vascular damage and
chronic atherosclerotic by increased production of ROS
by ANG II, additional mechanisms such as low-density
lipoprotein (LDL) oxidation and uptake, increased LDLreceptor expression (338, 494), increased expression of
molecular mediators of inflammation such as NF␬B or
cell adhesion molecules such as vascular cell adhesion
molecule (VCAM)-1 or intercellular adhesion molecule
(ICAM)-1 is involved (96, 161, 424, 526). In addition, chemokines and proinflammatory cytokines are activated
(96, 424). Moreover, apoptotic changes in response to
ANG II in the vascular wall have been described (162).
This, in addition to ANG II-induced modulation of extracellular matrix components by matrix metalloproteinases
(MMPs) and tissue inhibitors of MMPs (TIMPs), may play
a role in vascular remodeling (52, 312) including processes such as the disruption of the normal endothelial
layer in early atherosclerosis or plaque rupture in more
advanced atherosclerosis (102). Moreover, AT1 and AT2
receptors have been shown to induce opposing effects on
vascular smooth muscle cell growth (295). The AT2 receptor may again be considered as a balancing principle that
counteracts many of the mechanisms indicated above
that are mediated by the AT1 receptor. Percutaneous
transluminal coronary angioplasty (PTCA) injury in humans results in upregulation of ACE at sites of active
repair (509). After balloon injury of rabbit carotid artery
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during one pass through a hindlimb. This conversion was
abolished by ACE inhibition. Thus these data supported
the presence of a functional vascular RAS in which ACE
contributed to the local formation of ANG II. In subsequent experiments it was shown that the vascular production of ANG II was endothelium mediated, since the conversion of ANG I to ANG II was abrogated by endothelium
denudation (273).
In response to either systemically or locally generated ANG II, the AT1 receptor mediates the contractile
response by phospholipase C-dependent mechanisms
leading to an increase in intracellular calcium (142, 604).
It also acts indirectly, by stimulating the synthesis of
other vasoconstrictors such as endothelin-1 (535, 582,
614). In contrast, activation of AT2 receptors results in
activation of protein phosphatases, thereby reversing the
effects mediated by ANG II binding to AT1 receptors
(505). Thus the AT2 receptor appears to mediate mechanisms that are counterregulatory and prevent the occurrence of pathological vascular changes (77, 773). The
functional role of the AT2 receptor was primarily seen
during fetal development during which AT2 is highly expressed (639, 724). Subsequently, reappearance of AT2 in
the adult organism was associated with pathological
events that can be viewed as fetal-reprogramming. This,
however, does not rule out the possibility that AT2 plays
an important role for the regulation of vascular tone and
blood pressure under physiological conditions (39). Indeed, a large body of evidence obtained primarily in animals supports a role for AT2 receptor-mediated vasodilation (39, 234, 234, 758). Importantly, however, this vasodilatory role of AT2 has been also clearly demonstrated in
human coronary microarteries (38, 39), while the effects
in larger human coronary arteries (38) and human forearm resistance vessels (429) were not significant (38, 39).
Collectively, the vasodilatory effect mediated by AT2 receptors appears to be predominantly attributable to direct
activation of the nitric oxide (NO)-cGMP pathway, while
indirect activation of NO via bradykinin and B2 receptors
as mediators of AT2-induced vasodilation is less well established (39). However, recent experimental work in
hypertensive rats clearly demonstrates that AT2 receptormediated vasodilatation in vivo depends on the blood
pressure status (807). In addition to the modulation of
vascular tone by ANG II via the NO-cGMP pathway, research carried out during the last decade has clearly
shown that the effects of ANG II in the vasculature are
mediated at least in part by the modification of the redox
milieu of its target cells (253). ANG II has been shown to
activate the vascular NAD(P)H oxidase(s) resulting in the
production of reactive oxygen species (ROS), namely,
superoxide and hydrogen peroxide (71, 240, 253, 457, 565,
637, 714). Consequently, ANG II is capable of increasing
NO bioavailability by activation NO-cGMP pathway via
AT2 and decreasing NO bioavailability by promoting oxi-
PHYSIOLOGY OF LOCAL RENIN-ANGIOTENSIN SYSTEMS
7. Angiogenesis
Walsh et al. (757) indicated that ANG II can stimulate
angiogenesis, acting via AT1 receptors within the subcutaneous sponge granuloma model in the rat and that AT1
and AT2 receptors and ACE develop sequentially during
microvascular maturation. This confirms earlier reports
that ANG II stimulates angiogenesis in the chick embryo
model (387). These authors have also indicated that an
alternative ANG II receptor is mediating these changes
(386). It is unclear whether this alternative mechanism is
Physiol Rev • VOL
explained by the antiangiogenic actions of ANG-(1O7),
which can stimulate NO release by interaction with a
non-type 1 or type 2 ANG receptor (431). Studies in AT2deficient mice and wild-type mice using the surgically
induced hindlimb ischemia model indicated that AT2 confers an antiangiogenic effect that is associated with activation of apoptosis (655). This experiment would question the beneficial role of AT2 stimulation in the context of
pharmacological AT1 blockade in ischemic tissues (403).
Interestingly, Ac-SDKP, which is inactivated by ACE, has
been shown to promote neovascularization in the cornea
and capillary density in the heart (761).
8. Gender difference in cardiovascular RAS
The tissue RAS plays an important role in organs of
the reproductive system, and components of the RAS are
influenced by gender and sex hormones (207). A large
body of evidence has been obtained through research in
animals that components of the RAS are significantly
influenced by gender effects at the tissue levels (21, 182,
214, 216, 237, 274, 492, 495), while clinical studies in
humans have predominantly evaluated gender effects on
the circulating, i.e., systemic, RAS (98, 129, 235, 261, 262,
374, 625, 634). Overall, the role of RAS to explain genderrelated differences in the cardiovascular system has been
addressed by many studies in both animals and humans.
The characterization of an estrogen-responsive element in
the 5⬘-flanking region of the angiotensinogen gene has
been an important early finding to prove an interaction
with sex hormones and the RAS at the molecular level
(192, 237). In addition, angiotensinogen expression in the
liver is reduced by castration and increased by testosterone treatment in rats (182). While earlier studies suggested that renin activity in plasma is stimulated by estrogens, more recent studies indicated that renin is actually suppressed by estrogens (207, 508, 625). Castration of
male rats leads to reduction, while testosterone treatment
in ovariectomized female rats increased plasma renin activity (182). Collectively these studies are in line with the
observation that renin plasma levels are lower in women
compared with men (207, 625). However, the expression
of ACE mRNA was significantly lowered in response to
estradiol in kidney, lung, and aorta in rats (216). In the
heart, ventricular ACE is more abundant in male than
female mice at both mRNA and protein levels after reaching sexual maturity and with increasing age (214). Oophorectomy leads only to a slight increase in ACE levels in
female mice, whereas ventricular ACE levels are substantially decreased in androgen-deprived males (214). Thus
the antithetical changes in ventricular ACE abundance
seen in agonadal male and female mice suggest that testosterone as well as estrogen may play a role in regulating
ACE expression in the heart (214). In humans, circulating
ACE levels appear also to be lower in response to estro-
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and after pretreatment with perindopril, there was a reduced neointima formation (316). In contrast, Dale and
Blaine (127) have shown that enalaprilat has no effect on
neointimal growth or cell proliferation in a vascular organ
culture model of rabbit, which may be due to modelspecific effects. The blockade of the AT1 receptor reduced
also neointima growth in a manner similar to that of ACE
inhibition. The pretreatment with an AT2 receptor antagonist, CGP 42112A, did not change the neointima-media
ratio (127). The direct involvement of the AT2 receptor in
reducing neointima formation, however, has ultimately
been shown by direct gene transfer (463). The functional
importance of AT2 has indeed been supported by a study
demonstrating that chronic antagonism of AT2 receptors
led to severe vascular changes such as aortic aneurysms
and arteriosclerosis (136). The vascular changes in AT2
knockout mice were less dramatic but pointed in a similar
direction, since animals show elevated blood pressure
and an increased sensitivity for DOCA-salt hypertension
(241). The intracellular mechanisms of these changes
have been addressed in vascular smooth muscle cells
from AT2 overexpressing transgenic mice (441). The results of this study suggest that AT2 activation inhibits JNK
and c-Jun expression. However, conflicting results have
also been generated during the last decade, questioning
the beneficial role of AT2 stimulation in the vasculature,
particularly under pathological conditions (403, 404).
Levy et al. (404) demonstrated in normotensive Wistar
rats receiving hypertensive doses of ANG II that chronic
blockade of AT2 with the selective antagonist PD123319
had no effect on arterial pressure but antagonized the
effect of ANG II on arterial hypertrophy and fibrosis.
Moreover, chronic treatment with a selective AT1 antagonist lowered blood pressure but still led to smooth muscle cell hypertrophy and hyperplasia (404). These data
suggest that the detrimental in vivo effects of ANG II on
vascular remodeling may be mediated at least in part via
AT2. In this regard, AT2 may contribute to vascular adaptation and remodeling by influencing apoptosis in vascular smooth muscle cells (433). However, the effect of AT2
stimulation on vascular smooth muscle cells may differ
between different cell phenotypes (37) and on the coadministration of AT1 antagonists (706).
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MARTIN PAUL, ALI POYAN MEHR, AND REINHOLD KREUTZ
C. Nervous System
1. Central nervous system
The postulation of an independent brain RAS was
one of the first indications of the presence of local ANG
formation in tissues. Bickerton and Buckley (50) had
already shown in 1961 specific central ANG actions using
cross-circulation studies in the dog, and several authors
(202, 635) could demonstrate an interaction between ANG
II and the autonomous nervous system. These data soon
led to the identification of RAS components in the brain.
Physiol Rev • VOL
FIG. 2. RAS in the brain. Two possible ways of ANG II generation
within the CNS are discussed: 1) volume transmission: extracellular
generation of angiotensin peptides, acting as neurohormones; and 2)
wiring transmission: uptake of angiotensinogen by neurons and formation of peptides within the neuron. ANG II acts as neurotransmitter or
cotransmitter (528).
The existence and functional relevance of the brain RAS
is in the meantime fairly established (31, 592). The concept of local ANG synthesis in the brain is shown in
Figure 2.
A) RENIN. Renin activity within the brain was first reported by Ganten et al. (220). Although this novel concept
has been challenged by some authors (244), the initial
finding has been confirmed by studies on the subcellular
localization of brain renin in synaptosomes (530) as well
as gene expression studies. Renin mRNA was found in the
rat and mouse brain (176, 179) albeit at low levels of
expression (307, 513, 531, 692). Renin activity is present in
many brain regions of the rat and decreases with the age
of the animals (611). High expression levels of the recently identified prorenin/renin receptor were also detected in the brain (488, 490). Renin-like activity is high in
hypothalamus and pituitary and pineal glands from rat
(270), mouse (666), hog (276), as well as rat and dog (219).
Renin protein is measurable in rat primary cultures of
brain cells and neurons, and a strong staining in glia cells
(270) has been observed. Okamura et al. (512) demonstrated renin as well as ANG I and ANG II and ACE in
neuroblastoma cells. With the use of double or triple
immunogold labeling methods, angiotensinogen, prorenin, and renin were found in lactotrope, gonadotrope,
somatotrope, corticotrope, and thyrotrope glandular cell
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gens (558, 625, 634). Similarly, AT1 receptor is also downregulated by estrogens while estrogen deficiency leads to
upregulation of this receptor (492). In female transgenic
rats with activated tissue RAS, it was shown that estrogen
treatment is protective against hypertension, possibly by
amplifying the vasodilator contributions of ANG-(1O7),
while reducing the formation and vasoconstrictor actions
of ANG II independently of changes from plasma renin
activity (61). In summary, the net effect of estrogens
seems to result in a suppression of the RAS both systemically and at the tissue level (207). The role of testosterone or androgens has been less well characterized, although more recently Baltatu et al. (32) demonstrated
that treatment with the androgen receptor antagonist flutamide protects against hypertension and end-organ damage not only in male but also in female TGR(mREN2)27
rats.
Despite the evidence that both the activity of the RAS
and cardiovascular morbidity and mortality show gender
differences, it is not fully uncovered to what extent gender and sex hormones regulate the RAS and thereby
mediate effects on the cardiovascular system in men as
well as pre- and postmenopausal women during physiological conditions (207). Moreover, further study of this
issue appears of interest for several important issues of
clinical medicine such as cardiac and vascular remodeling
processes in cardiovascular diseases and with ageing as
well as the role of hormone replacement therapy (583). In
this regard, a more recent study is of interest investigating
the variation of the RAS in healthy, premenopausal
women during predefined phases of the normal menstrual
cycle (98). In this study it was shown that resting blood
pressures were lower in the luteal phase of the cycle with
high-estrogen phase (days 15–24) compared with the
low-estrogen phase of the cycle despite acute increases of
renin and aldosterone during the high-estrogen phase
(98). In addition, in postmenopausal healthy and normotensive women it was shown that estrogen replacement
therapy increases ANG II yet lowers blood pressure, thus
suggesting that compensatory mechanisms probably at
the tissue level may protect against the systemic activation of the RAS (260).
PHYSIOLOGY OF LOCAL RENIN-ANGIOTENSIN SYSTEMS
Physiol Rev • VOL
cortex but also in the superior colliculus, brain stem,
amygdala, cerebellum, hippocampus, and olfactory bulb
of rats (547). In this context, a gender difference between
the level of ANG II in male and female rat brains was
described. ANG II levels in male rat brains are consistently higher in all tissues except the olfactory bulb. ANG
II immunoreactivity was found in neurosecretory magnocellular cell groups of the hypothalamus, particularly in
paraventricular nucleus, supraoptic nucleus, as well as
different accessory cell groups using immunocytochemical methods (574). This suggests the existence of an
intrinsic hypothalamic and a hypothalamo-neurohypophysial system, since the fibers from the neurons of the
accessory nuclei project directly to adjacent blood vessels and do not comigrate with the hypothalamo-neurohypophysial fiber pathway (574).
Schiavone et al. (612) reported that the peptide ANG(1O7) is the major metabolite of dog brain stem homogenates both in the absence and in the presence of angiotensin-converting enzyme inhibitors. These data raised
the possibility of a functional role for ANG-(1O7) in the
brain. Subsequent studies in the in vitro hypothalamoneurohypophysial system of the rat demonstrated that
ANG-(1O7) is equipotent with ANG II in its activation of
arginine vasopressin (AVP) release (193, 203).
ANG-(1O7) was found in rat neurons in the supraoptic
nucleus, and in the anterior, medial, and lateral parvocellular, and posterior magnocellular subdivisions of the
paraventricular nucleus (363). Three-dimensional reconstructions showed that cells immunoreactive to ANG(1O7) and vasopressin were specifically codistributed in
the supraoptic nucleus and in the posterior magnocellular
subdivision of the paraventricular nucleus, suggesting
that ANG-(1O7) and vasopressin are colocalized and
coreleased.
E) ANGIOTENSIN RECEPTORS. The presence of receptors for
ANG has been amply demonstrated in rat brain tissue
(662, 717–720).
Strong AT1B receptor mRNA expression coincided
with low AT1A receptor mRNA expression in the anterior
pituitary of rat, and both receptor mRNAs were detected
in the hippocampus, cingulate cortex, and choroid plexus
of rat brain (325). Baltatu et al. (33) have detected that in
rat pineal gland AT1B mRNA expression exceeded the
expression AT1A mRNA and was colocalized with the
pinealocyte-specific tryptophan hydroxylase. AT1A receptor mRNA but not AT1B or AT2 mRNA as expressed in the
subfornical organ and paraventricular nucleus of the rat
hypothalamus, and AT1B as well as AT1A mRNA were
found in the cerebral cortex and hippocampus of rat;
conversely, AT2 mRNA, but not AT1A or AT1B, was expressed in the medial geniculate nucleus and inferior
olive of rat (324).
AT2 mRNA was found in several thalamic nuclei,
medial geniculate nuclei, the nucleus of the optic tract,
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types of the rat anterior pituitary (742). The highest levels
were detected in lactotropes and gonadotropes.
B) ACE. ACE mRNA is expressed in choroid plexus,
caudate putamen, cerebellum, brain stem, and hippocampus of rat brain (772). ACE mRNA was also found in the
pineal gland of rat (33). The localization of ACE protein in
the brain was verified by quantitative autoradiography
(90, 445, 550, 683), with high levels in the choroid plexus,
blood vessels, subfornical organ, and organum vasculosum of the lamina terminalis, with somewhat lower levels
in the thalamus, hypothalamus, basal ganglia, and posterior pituitary gland. ACE colocalized with renin in synaptosomal fractions of these brain structures (530). By autoradiography the highest concentrations of ACE were
found in the choroid plexus, blood vessels, subfornical
organ, vascular organ of the lamina terminalis, area postrema, and inferior olive of the rabbit, and intermediate
levels of binding were found throughout the basal ganglia,
midbrain, central gray and the superior colliculus, solitary
tract nucleus, and dorsal motor nucleus of vagus (579).
C) OTHER ANG II FORMING ENZYMES. Possible enzymes involved in brain ANG formation are tonin (615), cathepsin
G (349), tissue plasminogen activator, and chymase (34).
Their ultimate functional role in brain ANG formation,
however, remains to be determined.
D) ANGIOTENSINOGEN, ANG I, AND ANG II. Angiotensinogen
mRNA was described in rat brain by Campbell et al. (72)
and Ohkubo et al. (511). Other investigators (427) verified
these findings using in situ hybridization and localized
angiotensinogen mRNA in rat cells that stained for glial
fibrillary acid protein, which is a marker for glial cells.
Baltatu et al. (33) also found that angiotensinogen mRNA
was colocalized with the astrocyte marker glial fibrillary
acidic protein in pineal glands from rats. Angiotensinogen
mRNA and angiotensinogen immunoreactivity were both
present in glial cell populations of all rat cerebellar layers,
especially in the Purkinje and granular cell layers and
within the cerebellar nuclei (419). Astroglia as a main
source for angiotensinogen synthesis were also shown by
other studies (65, 303). In contrast to these findings, some
studies have succeeded in demonstrating angiotensinogen also in pure neuronal cultures (269). High levels of
angiotensinogen and its mRNA are found in hypothalamus and brain stem (268, 427, 572). In dog brain, ⬃95% of
recovered angiotensinogen has been reported to be extracellular (466), and Thomas et al. (709) have demonstrated
the distribution of angiotensinogen in the rat brain by
immunocytochemistry. This is supported by findings that
the cerebrospinal fluid of dog and rat contains considerable amounts of angiotensinogen (455, 609).
The impermeability of the blood-brain barrier and
blood-cerebrospinal fluid barrier for ANG II was reported
by several authors (329, 610, 747). With the use of radioimmunoassay and HPLC analysis, ANG II was found with
the highest levels in the hypothalamus, pituitary, and
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MARTIN PAUL, ALI POYAN MEHR, AND REINHOLD KREUTZ
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was reported that astrocytes of rats express AT1 receptors. AT2 receptors were detected immunohistochemically within the hypothalamic paraventricular and the
supraoptic nuclei of the rat brain, and more specifically, in
neurons also containing vasopressin (642). But in those
structures there is a lack of AT2 binding using receptor
autoradiography, suggesting that AT2 receptors are transported to the posterior pituitary.
Using a gene targeting approach in mice, Davisson et
al. (137) have proposed that the AT1A receptor is mainly
involved in central blood pressure control while the AT1B
receptor is responsible for mediating the drinking
response.
AT4 receptors as ligands for ANG IV are located in
brain areas implicated in memory acquisition and retrieval, stress, and spatial learning (785). Specific ANG IV,
ANG-(3O8), binding sites were found in the forebrain, in
particular in the cortex, the hippocampus, the amygdala,
the thalamus, and the hypothalamus of mice (749). Rat
AT4 receptors were found in cerebral cortex, piriform
cortex, hippocampus, habenulae, colliculi, septum, periaqueductal gray, several thalamic nuclei, the arcuate nucleus of the hypothalamus, and cerebellum (575). The
authors have shown that after intracerebroventricular
(ICV) injection of ANG IV, Fos-like immunoreactivity was
present in the hippocampus and piriform cortex and that
this effect is only blocked by a specific AT4 receptor
antagonist. In sheep spinal cord, a high density of ANG IV
binding sites was localized to the perikaryon and processes of all somatic motor neurons, the autonomic motor
neurons in the lateral horns of thoracic and lumbar segments and all dorsal root ganglia and also in numerous
motor-associated regions at the supraspinal level, with
weaker binding observed in the sensory regions (452). In
macaca fascicularis brain, AT4 receptor binding sites
were found in motor nuclei and motor-associated regions
as ventral horn spinal motor neurons, all cranial motor
nuclei including the oculomotor, abducens, facial and
hypoglossal nuclei, and the dorsal motor nucleus of the
vagus, in the vestibular, reticular and inferior olivary nuclei, the granular layer of the cerebellum, and the Betz
cells of the motor cortex with moderate receptor density
in all cerebellar nuclei, ventral thalamic nuclei, and the
substantia nigra pars compacta; abundant AT4 receptors
are also found in the areas associated with cholinergic
nuclei and their projections, including the nucleus basalis
of Meynert, ventral limb of the diagonal band and the
hippocampus, somati motor nuclei, and autonomic
preganglionic motor nuclei (454).
There is still the possibility that we have not yet
discovered all relevant ANG II receptors. In the gerbil
brain and pituitary, most of the ANG II receptors are
different from AT1, AT2, and AT4 subtypes (149).
The Mas protooncogene, a heptahelical receptor in
search of a specific ligand, has been proposed as a medi-
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the subthalamic nucleus, the interposed nucleus of the
cerebellum, and the inferior olive of rat (323).
Expression of AT1B receptor mRNA was present in
33% of rat anterior pituitary cells, predominantly expressed by lactotropes and to a lower degree by corticotropes and is not detectable in somatotropes, mammosomatotropes, gonadotropes, or thyrotropes (385), in contrast to the distribution of angiotensinogen, prorenin, and
renin in the anterior pituitary.
High ANG II binding sites were found in medulla,
hypothalamus, and circumventricular organs of rat (222).
Moderate to strong AT1A labeling was found in the anterior olfactory nucleus, the piriform cortex, and the nucleus of the lateral olfactory tract (384). With the use of
immunohistochemistry, the AT2 receptor was detected in
the locus ceruleus, bed nucleus of the accessory olfactory
tract, and cerebellum in association with the Purkinje cell
layer, and the deep cerebellar nuclei of the rat brain
further structures were hippocampus, limbic structures,
thalamic areas, and hypothalamic areas (570). In the
mouse brain AT1 and AT2 receptor distribution was similar to that of the rat, with some notable exceptions, such
as the presence of AT1 but not AT2 receptors in the locus
cerulus and the expression of AT1 receptors in the caudate putamen (264). MacGregor et al. (430) have shown
that the ANG II binding sites in all forebrain, midbrain,
pontine, medullary, and spinal cord sites, as in the small
and large arteries in the adjacent meninges and choroid
plexus of the human was of the AT1 subtype. And both
AT1 and AT2 receptors occur, in contrast to the rat, in the
molecular layer of the cerebellum. AT1 immunoreactivity
was detected in several hypothalamic nuclei, substantia
nigra, locus ceruleus, nucleus tractus solitarius, ventrolateral medulla, pontine nuclei, and inferior olivary nucleus
of the human brain (44). Brain ANG II receptors are
differentially regulated by a number of stimuli. Chemical
lesions of the young rat inferior olive reduced ANG II
binding to AT2 receptors and AT2 receptor mRNA levels in
this area by 50% and produced a similar decrease in AT2
receptor binding in the molecular layer of the cerebellar
cortex (322). The extent of binding reduction was similar
3 and 7 days after the lesion. Interestingly, the authors
have detected only AT2 binding sites in the molecular
layer and not AT2 receptor mRNA. The lesions did not
change ANG II binding to AT1 receptors in the molecular
layer or AT1 receptor mRNA levels in Purkinje cells; also
AT2 receptor binding and AT2 receptor mRNA levels in
the deep cerebellar nuclei were not affected according to
the authors. A weak, diffuse cytoplasmatic AT1 receptorlike immunoreactivity was observed in almost all the
catecholaminergic cell bodies of the A2, C1, C2, and C3
cell groups of rat, except those of the A1 cell group (801).
In addition, the AT1 receptor-like immunoreactivity was
seen in noncatecholaminergic neurons. With the use of
electrophysiological (287) and autoradiographic studies it
PHYSIOLOGY OF LOCAL RENIN-ANGIOTENSIN SYSTEMS
Physiol Rev • VOL
affect the central sensitivity of the cardiac sympathetic
afferent reflex or the baseline hemodynamics, but the
baseline of renal sympathetic nerve activity increased
during the infusion of ANG II (428). However, chronic ICV
infusion of ANG II enhanced the central sensitivity of the
cardiac sympathetic afferent reflex via AT1 receptor. In
addition, chronic ICV infusion of ANG II elicited an increase in arterial pressure. In mice, the blood pressure
increase elicited by centrally administered ANG II is most
likely due to AT1A receptor activation (137). However, the
drinking response requires the presence of AT1B
receptors.
Increased AT1 expression in the brain has been suggested as an early marker for the development of hypertension. AT1 protein levels were higher in the brain stem
of the Zucker obese rat (53), a rat model with a predisposition for hypertension. An ICV injection of ANG II in
these rats caused a significantly greater increase in blood
pressure compared with control animals. Similar changes
are seen in other cardiovascular disorders. Higher binding
densities for AT1 receptor were found in the subfornical
organ, paraventricular hypothalamic nuclei, and solitary
tract nuclei in rats with chronic heart failure compared
with controls (803). Thus, in rats with chronic heart failure, AT1 expression is increased in brain regions that are
closely related to water intake, vasopressin release, and
hemodynamic regulation.
In rat hypothalamus there is an inhibitory effect on
noradrenergic neurotransmission caused by ANG-(1O7)
which has been suggested to be mediated by the AT2
receptor (229). Furthermore, inhibition of NO synthase
(NOS) prevented this effect, suggesting the involvement
of NOS-related mechanisms. Rats pretreated with NGnitro-L-arginine methyl ester (L-NAME), a NOS inhibitor,
showed a greater pressure response to ANG II microinjection into the rostral ventrolateral medulla, than in rats
without L-NAME treatment (716). Microinjection of the
AT1 receptor antagonist CV11974 into the depressor region within the nucleus tractus solitarii of rat produced
greater decreases in arterial pressure, heart rate, and
renal sympathetic nerve activity in L-NAME-treated rats
than in control rats (188). In addition, ACE mRNA levels
in the brain stem were greater in L-NAME-treated rats
(188).
The brain RAS is closely linked to central vasopressin
actions. The transgenic rats with reduced (⫺90%) brain
angiotensinogen levels described above exhibit a diabetes
insipidus-like syndrome producing an increased amount
of urine with decreased osmolarity (616). There was also
a reduction in plasma vasopressin by 35% in these animals. Kagiyama et al. (330) suggested that the reduction
of angiotensinogen in rats plays important roles in vasopressin release and sympathetic nerve activity but may
not contribute to the maintenance of arterial pressure in
hypertensive rats. ICV administration of ANG II and ANG
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ator of ANG II-related effects in the brain (15, 311). While
it appears unlikely that Mas is a specific receptor for ANG
II, it has been suggested as an enhancer of AT1-mediated
effects in the brain (750). Aside from this functional interaction, Mas could also act as a specific receptor for
alternative ANG peptides such as ANG-(1O7), which
should be verified. Knock-out studies of Mas showed that
it plays an important role as a modulating factor in the
electrophysiology of the hippocampus (759).
F) FUNCTION. I) Blood pressure regulation. The brain
RAS appears to play a prominent role in central blood
pressure regulation. There is increased activity of renin in
several nuclei of the brain stem and in neurohypophysis
of young hypertensive rats when compared with agematched normotensive control animals (611). The higher
renin mRNA concentration in the brain stem of SHR
appears to be at least partially determined by the genotype of the renin gene (648). The binding activity of AGE
2 (angiotensinogen gene activating element) and angiotensinogen mRNA levels were higher in the brain of spontaneously hypertensive rats (SHR) compared with controls (500). In hypertensive rats (SHR) there were also a
significantly higher numbers of measurable AT1 and AT2
receptor subtypes in the hypothalamus compared with
controls (252). This is not a secondary phenomenon, since
transgenic approaches leading to a permanent reduction
of angiotensinogen in the brain show opposite characteristics. Basal systolic blood pressure was significantly
lower in transgenic rats with permanent inhibition of
brain angiotensinogen synthesis compared with controls
(35, 616). Mice lacking the AT2 receptor gene have an
increase in blood pressure and increased sensitivity to
pressure effects of ANG II (298). Chronic subcutaneous
administration of CV-11974, an AT1 receptor antagonist,
shifted the brain autoregulation curve toward lower blood
pressures in rats and markedly decreased the expression
of AT1 receptors both in areas outside the blood-brain
barrier (subfornical organ, 95% decrease) and inside the
blood-brain barrier (nucleus tractus solitarius, 87% decrease, and paraventricular nucleus, 96% decrease) (503).
It has been reported that ANG II can increase blood
pressure when administered directly into the brain (50).
This action could be partially due to an interaction with
the sympathetic nervous system. Bilateral microinjection
of ANG II and ANG III into the nucleus tractus solitarii
significantly and dose-dependently suppressed the
baroreceptor reflex of rats (426). The suppressive effect
of ANG II was reversed by coadministration of the AT1
receptor antagonist losartan.
The intraventricular infusion of ANG II in conscious
normotensive rabbits decreased cardiac baroreflex gain
by 20 –37%, whereas losartan infusion increased baroreflex gain by 24 –58%; blood pressure and heart rate were
not altered by any treatment (221). Acute infusion of ANG
II into dog cerebroventricular region of the brain did not
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MARTIN PAUL, ALI POYAN MEHR, AND REINHOLD KREUTZ
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In cattle, ICV infusion of losartan induced a dosedependent inhibition of the high water intake caused by
water restriction or by ANG II infusion but did not affect
salt appetite (51). Treatment with saralasin, a nonselective ANG II receptor antagonist, into the median preoptic
nucleus area of rats produced significantly attenuated
saline intake, but had no effect on water intake (703). In
addition, the direct injection of ANG I into the rat subfornical organ stimulated drinking, which was blocked by
losartan pretreatment (791). Prior administration of losartan into rat supraoptic nucleus decreased water and sodium intake induced by the injection of ANG II into the
medial septal area of water-deprived rats (18). This effect
was not seen by administration of PD123319, an AT2
receptor antagonist, applied directly into the supraoptic
nucleus. AT2 receptor stimulation inhibits drinking response and vasopressin release following centrally administered ANG II in rats (283).
Dehydration differentially upregulates angiotensinogen and AT1A receptor mRNA formation in distinct regions of the rat subfornical organ (36). ICV administration
of losartan completely blocked water intake caused by
ICV administration of ANG II, and following food deprivation, food intake was reduced by PD123319. Interestingly, neither water intake after water deprivation nor
sodium intake after sodium depletion were altered by
losartan or PD123319 (768). ANG II microinjected into the
organum vasculosum prelamina terminalis increased water consumption but did not induce intake of a hypertonic
NaCl solution. Again this effect was antagonized by losartan (181). The dose-response curve for water intake after
ICV injections showed a higher sensitivity to ANG II in
transgenic rats with specific downregulation of astroglial
synthesis of angiotensinogen compared with controls
(458).
Water deprivation upregulates AT1 binding and
mRNA in rat subfornical organ and anterior pituitary
(598). Following direct stimulation of the rat paraventricular nucleus with hyperosmotic solutions, concentration-dependent increases in ANG II immunoreactivity
were found (561). The centrally induced natriuresis and
blood pressure response to hypertonic saline that is ICV
administered involves AT1 receptors in the subfornical
organ of rats (580).
III) Function of the blood-brain barrier. The local
RAS in the brain is thought to play a functional role in the
maintenance of the blood-brain barrier. Angiotensinogen
but not renin levels in the brain appear to be relevant for
this function, since a decrease in density in granular layer
cells of hippocampus and an impaired blood-brain barrier
function which is seen in angiotensinogen-deficient mice,
whereas renin-deficient mice do not show this phenotype
(799). Other studies in knock-out mice came to similar
conclusions. Astrocytes of angiotensinogen knockout
mice had very attenuated expression of glial fibrially
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III in rats significantly increased renal plasma flow, glomerular filtration rate, urine flow, absolute and fractional
excretions of sodium and potassium, and decreased renal
efferent nerve activity; in higher levels, it also increased
blood pressure (94). ANG II produced antidiuretic effects
in a dose-dependent manner when microinjected into the
supraoptic and paraventricular nuclei of rats (593). This
effect is reduced by pretreatment with a vasopressin
antagonist.
Pharmacological inhibition of the brain RAS has beneficial effects in the brain. Intracerebroventricular infusion of captopril significantly attenuates the pressor response produced by systemically infused ANG I (576).
Losartan injection into the anterior hypothalamic preoptic area produced a depressor response in SHR and
DOCA-salt hypertensive rats but not in normotensive
Wistar-Kyoto rats, whereas ANG II injection into the same
area produced a pressor response in sham-operated,
Wistar-Kyoto rats, SHR and DOCA-salt hypertensive rats,
and the pressor response to ANG II was greater in DOCAsalt hypertensive rats and SHR than that in sham-operated
rats and Wistar-Kyoto rats (365). There was also a greater
release of ANG peptides in the anterior hypothalamic
preoptic area of DOCA-salt hypertensive rats as in the
anterior hypothalamic preoptic area of sham-operated
rats. The ACE inhibitor imidapril reduced edema formation in the cortex, hippocampus, and striatum of rats
suffering from stroke (792), and the progression of neurological deficits with loss of learning ability was suppressed. Treatment of stroke-prone SHR rats with perindropil prevents stroke through the suppression of blood
pressure elevation and prevention of tissue damage in the
brain (762). Nishmura et al. (502) have shown that pretreatment with the AT1 antagonist candesartan protected
hypertensive rats from brain ischemia by normalizing the
cerebral blood flow response, most likely through AT1
receptor blockade in cerebral vessels and in brain areas
controlling cerebrovascular flow during stroke.
II) Drinking and food intake. Epstein et al. (185)
discovered that ANG II elicited drinking when centrally
administered into the brain of the rats. ICV administration
of renin to rats also induced vigorous drinking behavior
(790). These effects are reduced when renin-injected rats
were pretreated with captopril. Other studies showed that
the ICV infusion of captopril completely blocked the
drinking response produced by systemically infused ANG
I (576). Conversely, a high sodium intake increased the
renin mRNA in the rat hypothalamus, despite the lowering
in renal renin mRNA (501) showing the independent regulation of the brain RAS by this stimulus. Chronic ICV
infusion of ANG II into the dog elicited an increase in
water intake (428). ICV infusion of losartan reduced postprandial drinking in sheep but did not affect food intake,
while the intravenous administration had no effect on
drinking (440).
PHYSIOLOGY OF LOCAL RENIN-ANGIOTENSIN SYSTEMS
Physiol Rev • VOL
and paraventricular nucleus, whereas c-Jun expression
was restricted to the median preoptic area, subfornical
organ, and paraventricular nucleus, and JunB was only
induced in the median preoptic area and subfornical organ. Losartan prevented the ANG II-induced immediate
early gene protein expression. Also the direct injection of
ANG I into the rat subfornical organ induced Fos immunoreactivity in the anterior third ventricle and in the
vasopressin neurons of the supraoptic and paraventricular nuclei, which was blocked by losartan pretreatment
(791). ANG II produced an upregulation of the AT2 mRNA
level in rat cortical neurons (645). This was blocked by an
AT2 receptor antagonist. It has also been shown that
growth hormone upregulates AT1A receptor in primary
cultures of rat astrocytes by a transcriptional mechanism
(788). AT2 stimulation promotes differentiation and axonal regeneration and inhibits proliferation of neuronal
cells (421, 443, 674). ANG II induces increased elongation
of neurites and cell migration in microexplant cultures of
the cerebellum from 3-day-old rats via activation of AT2
receptors (112). Furthermore, the authors have shown an
increase in expression of neurite-specific ␤-III-tubulin and
microtubule-associated proteins tau and MAP2 and that
AT1 receptor inhibits the AT2 effect. In another study the
same authors (113) were able to demonstrate that ANG II,
via the AT2 receptor, induces nitrite formation from NO
which was abolished by L-NAME. Furthermore, the treatment of the neuronal cell culture with SNAP, an exogenous source of NO, induced the same morphological differentiation. Other mechanisms that could be responsible
for AT2-related effects include stimulation of the serine/
threonine phosphatase A2 and inhibition of MAP kinases
Erk1 and Erk2 (292). AT2 receptor upregulation may be
involved in apoptosis and tissue repair after stroke, since
AT2 receptor gene expression was found to increase in
the infarct cortex of rats with permanent occlusion of the
middle cerebral artery (810). Additional data emerged
that lend further support to the idea of the involvement of
local RAS in tissue death after stroke. A recent study
reported a decrease in infarct volume and cerebral edema
of rats after reperfusion injury when animals, without
affecting systemic hemodynamics, were treated with an
ACE inhibitor (289).
Neurons cultured from newborn rat hypothalamus
and brain stem undergo apoptosis when exposed to ultraviolet (UV) radiation. This effect is enhanced by ANG II
and can be blocked by the AT2 receptor antagonist
PD123319 (644). Additionally, ANG II enhanced the UV
radiation-induced decrease in the levels of the DNA repair
enzyme poly-(ADP-ribose) polymerase. The MAP kinases
in the rat brain neuronal cultures are activated by AT1
receptors and inhibited by AT2 receptors, again pointing
to dual functions of these receptors (292).
VI) Temperature regulation. AT2-deficient mice exhibited a lower body temperature compared with controls
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acidic protein and decreased laminin production in response to cold injury, and ultimately incomplete reconstitution of impaired blood-brain barrier function (331).
These data are in contrast to reports by Rose et al.
(581) who suggested AT1 receptor-mediated uptake and
transport of ANG II at the site of the bovine blood-brain
barrier. This has been questioned since there is no evidence that angiotensins cross the blood-brain barrier and
penetrate noncircumventricular organ structures (256).
Monti et al. (458) found functional upregulation of
the AT1 receptors inside the blood-brain barrier in a transgenic rat line with specific downregulation of astroglial
synthesis of angiotensinogen. The authors have found a
higher AT1 receptor binding in most of the regions inside
the blood-brain barrier in transgenic rats compared with
controls. In contrast, in the circumventricular organs investigated, AT1 receptor binding was significantly lower
in transgenic rats.
IV) Central actions on the reproductive system. In
the pituitary of female rats, mRNA levels for angiotensinogen were increased by 45% following estrogen administration (346). These authors also demonstrated that estradiol caused a 30 – 40% reduction in the levels of AT1 mRNA
in pituitary and hypothalamic-thalamic areas of the female rat. A reduction in ANG II binding to AT1 receptors
in the pituitary and the subfornical organ was measured
following estrogen treatment. AT1A receptor mRNA expression is induced by estrogen-progesterone in dopaminergic neurons of the female rat arcuate nucleus (326).
ANG II immunoreactivity into rat cerebrospinal fluid was
greater on proestrus compared with diestrus day 1, and in
the overall comparison of ANG II immunoreactivity was
released from the preoptic-anterior hypothalamic area,
significantly more ANG II immunoreactivity was released
on the day of proestrus versus diestrus day 1. ANG II
increased prolactin release and produced an immediate
spike of intracellular Ca2⫹ followed by a plateau in cells
from rat pituitary (158). These effects were blocked by
losartan but not by PD123319, confirming the functional
link of the system.
V) Induction of transcription and translation. Central RAS stimulation induces a program of transcription
factors commonly associated with the regulation of neuroplasticity. ICV administration of renin to rats induced
Fos and Egr-1 immunoreactivity in the subfornical organ;
median preoptic, supraoptic, and paraventricular nuclei;
area postrema, nuclei of the solitary tract; and lateral
parabrachial nuclei (790).
Similar findings have been described by Lebrun et al.
(378), who after ICV ANG II infusion in rat brain found a
dose-dependent expression of c-Fos and Krox-24 in the
subfornical organ, the median preoptic area, and the paraventricular nucleus and supraoptic nucleus of the hypothalamus. Furthermore, FosB expression was induced
after ICV injection of ANG II in the median preoptic area
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MARTIN PAUL, ALI POYAN MEHR, AND REINHOLD KREUTZ
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neously observed decreased in brain 5-HT levels, suggesting a cross-link to the serotonergic system (746).
Sakagawa et al. (591) have shown that the pain threshold
was significantly lower in AT2-deficient mice, compared
with findings in wild-type mice, and that the fluorescence
intensity of ␤-endorphin in the arcuate nucleus of the
medial basal hypothalamus was significantly lower in AT2deficient mice, compared with findings in wild-type mice.
Furthermore, the authors found that the AT2 receptor
does not influence learning behavior and brain edema
formation.
Dexamethasone injection in rats caused an increase
in AT1 receptor mRNA in the hypothalamic paraventricular nucleus, and AT1 mRNA is also increased after exposure to stress paradigms associated with activation of the
hypothalamic-pituitary adrenal axis (6).
2. Peripheral nervous system
A) SYMPATHETIC NERVOUS SYSTEM. ANG II binding sites were
localized and quantified in rat stellate and superior cervical ganglia by quantitative autoradiography (85). High
densities of AT1 receptors in sheep (516) and ANG II
immunoreactive terminals in guinea pig and rat (215, 414)
occur in the intermediolateral cell column of the spinal
cord and the central autonomic area.
A direct relationship between the effect of ANG II
and the sympathetic nervous system is likely since sympathectomy or reserpine treatment attenuates the blood
pressure response to ANG II. Intrathecal administration
of ANG II increases sympathetic vasomotor nerve discharge and blood pressure in rats (688). The interaction of
ANG II with postganglionic nerve terminals was shown by
Day and Owen (138). In addition, Lewis and Reit (406)
have shown that ANG II potentiates sympathetic transmission through the sympathetic ganglia of the cat.
ANG II is able to increase the excitability of superior
cervical ganglia cells (640) and cells from sympathetic
region of the thoracic and lumbar spinal cord or rat (405).
Cox et al. (117) have shown that ANG II and ANG III were
able to facilitate the action potential-induced release of
norepinephrine via a prejunctional AT1 receptor in mouse
atria and spleen. In the rat, ANG II caused an increased
sodium and water absorption that is mediated by increased norepinephrine release from sympathetic neurons (400).
Upregulation of ANG II release and angiotensinogen
mRNA expression can be induced by high-frequency
preganglionic stimulation at the canine cardiac sympathetic ganglia (369). The resulting positive chronotropic
responses were inhibited by the nonpeptide AT1 receptor
antagonist forasartan or the ACE inhibitor captopril,
while the increase in heart rate elicited by postganglionic
stellate stimulation could not be inhibited by these compounds (369).
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and show smaller hyperthermia after intraperitoneal injection of interleukin-␤ and greater increase in body temperature and physical activity after nonimmunological
stress (766), suggesting a role for the brain RAS in temperature regulation.
VII) Motor control. Either bilateral or unilateral microinjections of ANG II into the hippocampal CA1 area of
rats affected locomotor activity in a dose-related
U-shaped manner (41, 42). The effect was more pronounced when ANG II was microinjected into the left CA1
area.
VIII) Visual system. Microinjection of ANG II in the
superficial layers of the superior colliculus of rat yielded
a strong reduction in the amplitude of visual evoked
potentials in a dose-related manner (114). Merabet et al.
(446) have shown that in rat this is predominantly mediated by AT1 receptor (446).
IX) Behavior and emotions. Belcheva et al. (43)
suggested that ANG II facilitates learning and memory of
rats, especially when microinjected into the left CA1 hippocampal area. Winnicka (777) has detected that bilateral
6-OHDA lesions to rat central amygdala (CA) totally abolished the facilitatory effect of ICV infusion of ANG II on
the retrieval process in a passive avoidance situation
(777). ANG II significantly increased the amplitude of field
potentials, of the rat lateral nucleus of the basolateral
amygdala, induced by the electrical stimulation, whereas
ANG IV caused a significant decrease in the amplitude of
field potentials (748). Wright et al. (786) suggested that
the brain ANG IV-AT4 system plays a role in the formation
of spatial search strategies and memories, since the AT4
receptor is heavily distributed in the CA1-CA3 regions of
the hippocampus, and chronic ICV administration of AT4
agonist (Norleucine1-ANG IV) facilitated the rate of acquisition to solve the spatial learning task. ANG II and
ANG-(3O7) improved object recognition in sham-operated rats to nucleus accumbens septi and to nucleus septi
lateralis, and bilateral 6-OHDA lesions to nucleus accumbens septi totally abolished and to nucleus septi lateralis
attenuated the facilitatory effect of both ANG peptides on
object recognition (778). This suggests that dopaminergic
projection to the septum mediale mediates facilitatory
effect of angiotensins on recognition memory in rats
(778).
Mice lacking angiotensinogen displayed the reduction of “depressive-like” behavior in the behavioral despair swim test and spontaneous locomotor activity diminished; however, they showed no axiogenic-like or
memory-deficit behavior, and there was no change in the
pain threshold (515). This was confirmed in other studies
where mice lacking angiotensinogen show no differences
compared with controls in anxiety and learning (760).
However, transgenic rats with diminished angiotensinogen production showed more signs of anxiety than control animals. An effect most likely due to the simulta-
PHYSIOLOGY OF LOCAL RENIN-ANGIOTENSIN SYSTEMS
D. Reproductive Tract
1. Female reproductive tract
As reviewed by Hagemann et al. (249), renin has been
detected in the uteroplacental unit of many species. Skinner et al. (660) showed that all parts of the human uteroplacental unit contain renin, with the highest concentrations found in the fetal membranes (chorion and amnion)
and decidua. In humans, prorenin is the major form of
renin in the uteroplacental unit (332, 765). Secretion of
prorenin from the human uteroplacental unit (57, 388)
and the corpus luteum (151) may explain the increased
plasma prorenin concentrations in pregnant women,
which is more pronounced in the first trimester (632).
A) OVARY. A schematic representation of the localization of RAS components in the ovary is shown in Figure 3.
Physiol Rev • VOL
FIG. 3. RAS in the ovary. Renin, synthesized and secreted by theca
cells, leads to local ANG production. Two possible ways in which ANG
II may modulate atresia in ovaries has been suggested: 1) ANG II is
acting on the AT2 receptor within the same follicle by an autocrine
mechanism leading to apoptosis and atresia; and 2) ANG II is secreted
by preovulatory follicles causing apoptosis in adjacent atretic follicles
(paracrine mechanism). Follicular fluid contains high levels of renin and
ANG II.
I) Renin. Ovarian renin mRNA was detected by several authors (304, 341, 411). Renin mRNA is expressed in
the corpora lutea of the rat but not in theca or granulosa
of follicles. Follicle-stimulating hormone stimulates renin
mRNA expression in the ovary of rat (342) and monkey
(304).
The ovary is the major source of plasma prorenin in
women (230). The rat ovary contains a moderate amount
of prorenin and renin activity, which are increased by
pregnant mare serum gonadotrophin (497). Renin is differentially expressed across species borders. Bovine corpora lutea express high levels of renin activity, while
porcine corpora lutea have very low levels of renin activity (496). In the cow, ovarian follicles contain prorenin
and renin, with the highest level of prorenin expression in
atretic follicles (469, 624). Lightman et al. (411) detected
renin mRNA in the gonadotropin-stimulated rat corpus
luteum using in situ hybridization histochemistry. No positive signal was detected in theca or granulosa cells.
Howard et al. (290) suggested that renin activity, which
varies with the estrous cycle, arises from theca or interstitial cells of the rat ovary. As mentioned above, Itskovitz
et al. (304) could detect renin mRNA in the theca of
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B) PARASYMPATHETIC NERVOUS SYSTEM. In vitro autoradiographic techniques demonstrate a high density of AT1
receptors in intracardiac ganglia and conduction systems
of rat heart (14, 590), but it is not known if they are
localized presynaptically or postsynaptically. Allen and
co-workers (11, 12) detected that ANG II receptors are
transported peripherally in the rat vagus nerve and may
well be localized on the terminals of parasympathetic
preganglionic neurons whose cell bodies lie in either the
nucleus ambiguus or dorsal motor nucleus of vagus in the
medulla. Diz and Ferrario (166) provided data that reveal
the existence of a mechanism for the bidirectional axonal
transport of ANG II binding sites in the cervical portion of
the vagus nerve of dogs.
Potter (556) has shown that ANG II inhibits release of
acetylcholine from the preganglionic neurons via a presynaptic mechanism in intact dogs and in isolated guinea
pig atria.
Ikegami et al. (300) showed that ⬃70% of hamster
submandibular ganglion neurons responded to ANG II
with persistent depolarization. This effect is mediated by
AT1 receptor subtypes. The AT2 receptor has been implied
in neurotropic effects in the peripheral nervous system,
since it could be demonstrated that AT2 effects promote
axonal regeneration after optic nerve crush in a tissue
culture model (421).
C) SENSORY NEURONS. There are suggestions that AT1 receptors are associated with a range of afferents nerves.
AT1 receptors were detected on cell bodies in nodose
ganglion, dorsal root ganglia, and the primary central
terminal regions of these neurons, the nucleus of the
solitary tract and dorsal laminae of the spinal cord of
several species (10, 11, 516). It has also been suggested
that AT1 receptors occur in the caudal nucleus of the
spinal trigeminal tract in the medulla (13) and that they
may be associated with the terminals of trigeminal sensory neurons.
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MARTIN PAUL, ALI POYAN MEHR, AND REINHOLD KREUTZ
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and on the epithelial cells of the fallopian tubes of the
nonpregnant sheep. ACE immunoreactivity showed a cyclic variation in the human endometrium with the highest
expression in the late secretory phase at the menses
(410).
Furthermore, the uterus contains cathepsin D (599)
and chymase (731), giving rise to possibilities for alternative pathways for ANG II formation in the uterus.
III) Angiotensinogen, ANG I, and ANG II. Angiotensinogen mRNA is expressed in spiral artery smooth
muscle in human uterine deciduas (459), but the stroma
of the uterus itself does not appear to produce angiotensinogen (218, 299). Immunoreactive ANG II was found
by Naruse et al. (479) in human uterus. Rat uterus also
contains immunoreactive ANG II (154). ANG II-like immunoreactivity was detected in human proliferative endometrium (glandular epithelium and stroma) with cyclic
changes (8). In the proliferative phase, ANG II immunoreactivity was expressed in the glandular epithelium and
stroma, whereas in the secretory phase intense immunoreactivity was seen in the perivascular stromal cells
around the endometrial spiral arterioles.
IV) Angiotensin receptors. Radioligand binding assays were used to demonstrate for the first time radioligand binding to an ANG receptor in uterine tissue (413).
In addition, the first study to demonstrate ANG II receptor
subtypes showed that the human uterus contains primarily the AT2 receptor subtype (771). ANG II receptors are
also present on uterine glands and at a low level in the
endometrium of the rat (668). Similar data were provided
for the mouse where ANG II receptors are abundant in the
mouse uterus and primarily of the AT2 subtype. Interestingly, in homogenates of the mouse uterus, the AT1 receptor predominates, which could be of vascular origin.
Since the connective tissue has been removed in this
study the authors suggested that AT2 receptor binding
seen in receptor autoradiographic studies is attributable
to binding to connective tissue rather than on other components of the uterus. Autoradiographic studies in the
mouse suggest that cervical AT2 receptor density is very
high. Again, as seen in the uterus, homogenates of mouse
cervix have relatively low levels of ANG II receptor
binding.
In the sheep uterus, AT1 and AT2 receptors are
present in the endometrium and myometrium, respectively (451). In late term pregnant sheep, myometrial AT2
receptors are replaced by AT1 receptors. In humans,
⬃90% of the ANG II receptors in the myometrium of
nonpregnant women are of the AT2 subtype (115). The
density of the ANG II receptors in the uterus of near-term
pregnant women decreases by ⬎90%, reflecting more than
a 95% loss of AT2 receptors.
C) OVIDUCT. I) ACE. ACE activity is present in the oviduct of chicken and pig and is localized in epithelial cells
of the oviduct in sheep (198, 451, 456).
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human chorionic gonadotropin (hCG) stimulated monkey
ovaries but not renin-like immunoreactivity, suggesting
that the product is immediately secreted. Unlike this finding in the human, renin-like immunoreactivity has been
observed in theca, stromal, luteal, and granulosa cells
(518, 519). Renin-like activity has also been found in
human follicular fluid (412).
II) ACE. ACE is abundant in the rat ovary (126). Rat
ovarian ACE is membrane bound and is present in the
germinal epithelium, capsule of the corpora lutea and in
many, but not all, follicles (669). In the human ovary, ACE
activity increases with age (187), which could be a result
of the age-dependent reduction in the number of ovulating follicles rather than a direct regulatory effect.
III) Angiotensinogen, ANG I, and ANG II. Angiotensinogen mRNA has been shown to be expressed in the
ovary of rat and mouse (511, 701). By immunocytochemistry, Thomas and Sernia (710) have found angiotensinogen activity in specific populations of granulosa cells of
the rat ovary and, to a lesser extent, in germinal epithelium, stroma, and luteal cells. The angiotensinogen presence appears to be greater in preovulatory follicles than in
atretic follicles. ANG II has been found in human follicular fluid (124, 412). Phillips et al. (546) reported that the
ovary contained the fourth highest level in 13 tissues
examined.
IV) Angiotensin receptors. The presence of AT1A
mRNA but not AT1B mRNA could be demonstrated in the
mouse ovary by Burson et al. (68). For the most part,
follicles that contain ACE also contain ANG II receptors.
In the rat, the follicular ANG II receptors are of the AT2
subtype and are located primarily on the granulosa and
theca interna cell layers of atretic follicles (135, 560, 667);
bovine ovaries contain also predominantly AT2 receptors
(64, 496). Rabbit ovaries express both AT1 and AT2 receptors, with the AT1 receptor being localized to the theca
and stroma and the AT2 receptor being expressed on the
granulosa cells (804). In contrast, Feral et al. (194) reported that only the AT1 receptor subtype was present in
the rabbit ovary and that it was localized on preovulatory
follicles. Autoradiographic receptor studies indicate that
the AT2 receptor subtype is the predominant ANG II
receptor subtype in the mouse ovary, with only a low level
of AT1 receptor expression (668).
B) UTERUS. I) Renin. Renin mRNA has been reported in
the endometrium, choriodecidua, and the fetal part of the
placenta (249) but not in the myometrium (299). Via immunocytochemistry, Raju and Lee (566) demonstrated
renin in the human endometrial glandular epithelium.
During late pregnancy, the uterus is also a source of
plasma prorenin (383).
II) ACE. The rat uterus expresses a low but detectable level of ACE (126), and Moeller et al. (451) found
ACE activity in high concentrations in the blood vessels of
the pregnant and nonpregnant sheep reproductive system
PHYSIOLOGY OF LOCAL RENIN-ANGIOTENSIN SYSTEMS
Physiol Rev • VOL
AT2 receptor, since an AT2 receptor antagonist
(PD123319) inhibited hCG- and ANG II-induced ovulation
and oocyte maturation in vitro, as well as ANG II-induced
estrogen and prostaglandin formation. But others (476,
539) using the same ANG II receptor antagonist, or an
ACE inhibitor were unable to fully replicate the inhibition
of ovulation. Steele et al. (677) also saw no impairment of
ovulation in rats that were systemically administered an
ANG II antagonist or an ACE inhibitor. The treatment of
women of child-bearing age for hypertension with the
ACE inhibitor enalapril did not affect normal cyclicity of
plasma gonadotrophins, gonadal steroids, or plasma prorenin (715). Life-long application of ACE inhibitors to rats
did not impair fertility (787). In contrast to this local
situation, there was a profoundly reduced ovulation by
ICV administration of ANG II receptor antagonist or ACE
inhibitor (677).
II) Uterus. Hagemann et al. (249) suggested that the
local function of ANG II on the uterus may be to control
uterine blood flow during pregnancy.
As might be expected, the contractile actions of ANG
II in the human uterus are mediated by AT1 receptors
(115, 619). The contractile response of the rat uterus to
ANG II and both AT1 and AT2 receptor density vary considerably over the estrous cycle (668).
2. Male reproductive tract
In the male reproductive system, local RAS function
is thought to be relevant for fertility. This system is regulated independently from the plasmatic RAS, and the
blood testicular barrier prevents that ACE inhibitors and
AT1 blockers affect fertility.
A) TESTES. A representation of the testicular RAS is
shown in Figure 4.
I) Renin. Renin mRNA was detected in mouse testis
by hybridization using cDNA and cRNA (173, 179, 522,
531) and RNase protection analyses (448). Further studies
(153) have shown the Leydig cells as an origin of this
tissue renin mRNA. Renin, ACE, ANG I, ANG II, and ANG
III were detected by both HPLC and radioimmunoassay in
purified Leydig cells from rat (523). Naruse et al. (478) did
provide immunohistological evidence for renin in human
Leydig cells.
II) ACE. The ACE gene encodes for two ACE proteins, the somatic ACE enzyme that has two identical
lobes and the testicular ACE molecule consisting of a
single lobe. The testicular ACE mRNA is transcribed from
the ACE gene by the tissue-specific choice of an alternative transcription initiation site as well as an alternative
polyadenylation site (291, 293, 367, 707). Bernstein et al.
(48) have demonstrated that mouse testicular ACE
(tACE) is encoded by a smaller mRNA (2,500 bases)
compared with the somatic ACE mRNA species found in
other organs such as kidney or lung (4,900 and 4,150
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II) Angiotensin receptors. Receptors for ANG II are
present in the human fallopian tube (600). While both AT1
and AT2 subtypes are present, the functional response to
ANG II, enhancement of tubal ciliary-beat frequency, was
mediated by the AT1 subtype. Receptor autoradiographic
studies of ANG II receptor binding in the mouse oviduct
indicate that they contain AT2 receptors, but at concentrations that are considerably lower than in the uterus
(668).
D) FUNCTION. I) Ovary. The RAS has been proposed as a
mediator of ovarian function and follicle maturation.
Mukhopadhyay et al. (468) have shown that prorenin
secretion from cultured bovine theca cells can be stimulated by luteinizing hormone. Hagemann (247) suggested
that secretion of prorenin from the ovary into the bloodstream is unique to humans. This group could also demonstrate that luteinizing hormone stimulates renin activity
in the follicular fluid of heifers (248). Also gonadotrophininduced stimulation of renin synthesis and release from
theca cells of bovine (63) and monkey follicles (304) has
been reported. Gonadotrophins are able to stimulate renin formation in the corpora lutea of the rat (155). The
authors suggested that angiogenesis of developing corpora lutea was due to the activation of the RAS in ovulatory follicles. However, the report that ANG II receptors
are not present on most preovulatory follicles (135) would
argue against a significant direct role of follicular fluid
ANG II in this angiogenic process. Moreover, recent observations suggest that vascular endothelial growth factor
is a primary angiogenic factor in the rat corpora lutea
(199, 668).
Fernandez et al. (196) observed that estrogen concentration and renin activity in human follicular fluid
were positively correlated, and others (305) have reported
that a high level of prorenin was associated with high
levels of testosterone in human immature follicle. ANG II
is able to induce estrogen release by in vitro pregnant
mare serum gonadotrophin stimulated immature rat ovaries, suggesting that ANG II promotes follicular maturation (559). In contrast, Morris et al. (467) suggested that
ANG II inhibited estradiol (tonic inhibition by endogenous ANG II) and increased progesterone formation in
human cultured luteinized granulosa cells and also increased testosterone in cultured rabbit theca cells in response to hCG (195).
Ovulation induced by pregnant mare serum gonadotropin in either immature rats or a perfused rat ovary
system was inhibited in the presence of an ANG II receptor antagonist. This inhibition could be overcome by administration of an excess of exogenous ANG II (539, 544).
In gonadotropin-treated rabbits, the nonselective ANG II
receptor antagonist saralasin is able to inhibit ovulation
(589). This effect could not be shown by inhibition of ACE
(543). Kuji et al. (366) reported that ANG II facilitates
follicular development and ovulation in the rabbit via the
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MARTIN PAUL, ALI POYAN MEHR, AND REINHOLD KREUTZ
bases). Molecular cloning of the human tACE cDNA indicates that the mRNA codes for 732 residues (vs. 1,306 in
endothelium) (375). tACE is equally active despite the fact
that it is translated from a shorter mRNA. Oligonucleotide
probes derived from tACE cDNA demonstrated expression of mRNA only in the testes and not in other organs
(772). Thus the tACE is highly tissue specific. Leydig cells
have been initially suggested as the primary source of
ACE in the testis (523), but further investigations have
confirmed that germinal cells are the origin of the tACE
activity. tACE is expressed at high levels by male germ
cells during spermiogenesis while somatic ACE is also
expressed in other testicular cells. The regulation of tACE
is tissue specific. Systemically administered ANG II decreased ACE mRNA levels in the lung and testis, but
unlike the pulmonary ACE activity, the tACE activity
shows negligible changes, suggesting that it is caused by
different half-lives of mRNA and/or protein (628).
The concentration of ACE in the testis is among the
highest in all organs (126). And before washout of seminal
fluid, ACE activity is higher in the testis than in epididymis and vas deferens, suggesting secretion of ACE into
seminal fluid (282). tACE activity was measured by Hohlbrugger et al. (282), and Berg et al. (45) have shown the
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FIG. 4. RAS in the testis. Location of ANG II forming pathways in
Leydig cells. Expression of the alternative testicular isoform of ACE
(tACE) in germ cells.
existence of pulmonary ACE in rabbit endothelial cells of
blood vessels in the interstitial tissue of testis by immunohistochemistry. In contrast to this finding, Strittmatter
and Snyder (684) could not detect any existence of ACE in
the interstitial tissue of rat testis.
III) Angiotensinogen, ANG I, and ANG II. Angiotensinogen mRNA was detected in testicular tissue in
some species. Dzau et al. (174) showed angiotensinogen
mRNA in mouse testis, whereas in rat testis angiotensinogen mRNA was undetectable. This goes along with a
report by Campbell and Habener (74) who could not
detect angiotensinogen mRNA in rat testis using Northern
blotting. Only when using a hybridization technique with
increased sensitivity (268) low amounts of angiotensinogen mRNA could be detected in rat testis.
IV) Angiotensin receptors. Targeted deletion of the
AT1B receptor gene in the mouse has shown high AT1B
gene transcription activities in testis (95), including mature and immature spermatic cells. Kitami et al. (347)
measured expression levels of AT1A and AT1B receptors in
rat testis by PCR and suggested that AT1A mRNA was
predominantly expressed.
Aguilera et al. (7) demonstrated the existence of ANG
II receptors in mature rat and rhesus monkey testis, indicating that ANG II receptors are located on the Leydig
cells. These results were confirmed by demonstrating the
localization of the AT1 receptor in rat Leydig cells by
immunofluorescence (743).
B) EPIDIDYMIS. The concept of ANG pathways and function in epididymis and sperm is shown in Figure 5.
I) Renin. The search for renin mRNA in this organ
was negative. Leung et al. (397) have not found any level
in rat epididymis using Northern blot and even more
sensitive RT-PCR assays.
II) ACE. ACE activity was measured in rat epididymis (282). Interestingly, epididymal tissue contains both
ACE isoenzymes. The somatic ACE isoform was localized
in rabbit epididymal blood vessels (45). It could also be
shown by these authors that epididymal tubular cells
contained pulmonary ACE, suggesting that spermatozoa
specifically express tACE. This has been supported by
other findings: when spermatozoa were prevented from
entering the epididymis by efferent duct legation, ACE
activity in the epididymis was greatly reduced (783).
III) Angiotensinogen, ANG I, and ANG II. Angiotensinogen mRNA was detected via RT-PCR and in situ
hybridization histochemistry in rat epididymal epithelium,
with the highest levels found in the epididymal tubules of
the cauda region (397). Using immunocytochemistry,
these authors localized precursor angiotensinogen protein in caput, corpus, and cauda of rat epididymis. The
concentrations of ANG I and ANG II are high in the rat
epididymal plasma compared with the concentrations in
the rete testis fluid and blood serum (783). Also, the level
of ANG II in the luminal fluid of the cauda epididymis was
PHYSIOLOGY OF LOCAL RENIN-ANGIOTENSIN SYSTEMS
markedly reduced after efferent duct ligation (783, 808).
With immunohistochemical staining, Zhao et al. (808) detected ANG II in rat epididymis with the highest level in
the basal cells of the cauda. The same authors suggested
a potential of the epithelial cells to secrete ANG II, since
ANG II could be detected by radioimmunoassay in the
supernatant of cultured endothelial cells.
IV) Angiotensin receptors. Leung et al. (392) provided evidence for the existence of ANG receptors in rat
epididymis. Both AT1 and AT2 were detected; however,
the immunostaining intensity for AT1 receptors was found
to be stronger than that for AT2 receptors, and the immunostaining for both receptors observed in the fully mature
rat epididymis was much more intense than that observed
in younger stages. The immunostaining was predominantly localized in the basal region. Grove and Speth (242)
have shown that rat epididymis contains functional ANG
II receptors. Also, Vinson et al. (743) have found AT1
receptors in epithelial tissue of rat epididymis. Autoradiographic analysis showed the presence of ANG II receptors
also in the rhesus monkey epididymis (7). Light microPhysiol Rev • VOL
scopic examination indicated that the binding of radiolabeled ANG II in the epididymis was associated with
smooth muscle cells.
C) SEMINAL PLASMA AND SPERMATOZOA. I) ACE. High ACE
activity has been determined in human seminal plasma
(739). The soluble ACE in seminal fluid resembles the
detergent-solubilized lung enzyme more than the detergent-solubilized testicular enzyme (150, 180). The active
enzyme in seminal fluid corresponds to the pulmonary
polypeptide (45, 372). These authors suggested that this
seminal fluid ACE may originate from cells of the epididymal tubules, particularly those of the vas deferens. Via
autoradiographic visualization with [3H]captopril, Strittmatter et al. (684) have shown high densities of [3H]captopril over spermatid heads, and in the lumen of seminiferous tubules also, the head of the epididymis demonstrates intense grain density at the luminal surface of the
epithelium with little luminal labeling by rats. The testicular ACE is expressed at high levels by developing germ
cells and is present in mature sperm (774). With the use of
indirect immunofluorescence and immunoperoxidase
methods, tACE was found in the seminiferous tubules of
the testes in spermatocytes containing mature spermatids, and in spermatids within the epididymal tubular
lumen in sexually mature, but not in immature, rabbits
(45), suggesting that the presence of tACE is dependent
on sexual maturation.
II) Angiotensin receptors. AT1 receptors were found
in primary spermatogonia and spermatid tails of rat testis
by Vinson et al. (743). These authors were able to confirm
this finding in ejaculated rat and human free swimming
sperm. Interestingly, they did not find any immunofluorescent activity from the spermatozoa in the lumen of rat
epididymis and from sperm isolated from the epididymis.
By targeting deletion of AT1B receptor gene in the mouse,
Chen et al. (95) have shown high AT1 transcriptional
activities in mature and immature spermatic cells, suggesting that AT1A can take over specific functions in these
knock-out animals or that other ANG receptors are involved in this process.
D) GLANDULA VESICALIS. I) ACE. High ACE activity has
been determined in human vesicula seminalis (739).
E) PROSTATE. I) Renin. Renin mRNA is present in mouse
prostate, and the human prostate shows a positive signal
after renin immunohistochemistry (478).
II) ACE. High ACE activity has been determined in
human benign prostatic hyperplasia, whereas normal
prostates apparently have low enzymatic activity (282,
739, 802). Other authors (735) have found higher levels in
the lateral and posterior prostate compared with ventral
prostate in rat, but the activity was still much lower than
that in epididymis.
III) Angiotensin receptors. Dinh et al. (164) reported
that in human prostate ANG II receptors were of the AT1
subtype and localized predominantly to periurethral stro-
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FIG. 5. RAS in the epididymis: intraluminal and intracellular generation of ANG II in the epididymis. Paracrine and autocrine secretion of
ANG II is mediated via the AT1 receptor. AT2 receptors may modulate
basal cell proliferation and differentiation. tACE may play an important
part in local modulation of fertility, but its exact role is unclear.
[Adapted from Zhao et al. (808).]
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MARTIN PAUL, ALI POYAN MEHR, AND REINHOLD KREUTZ
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AT1 and AT2 receptor concentration of rat testis with
predominant occurrence of AT1 receptors measured by in
vitro autoradiography (275). The concentration of rat AT1
and AT2 receptors at protein level is dependent on the
developmental stage. Total ANG II receptor binding (predominantly AT2 receptor) in the testis was highest at 1
day of age and decreased gradually thereafter, and the
4-wk-old rat testis contained almost exclusively AT1 receptors (334).
II) Epididymis. Anion and fluid secretion is stimulated by a number of peptide hormones, including ANG
(782). Previous electrophysiological studies demonstrated a higher potency of ANG II on the basolateral
surface in eliciting transient increases in short-circuit current when added to the basolateral as well as to the apical
surface of rat epididymal epithelium. ANG II secreted
from the basal cells may exerts its effect on electrolyte
transport by acting on ANG II receptors on the basolateral
membrane of the principal cells, which are largely responsible for the electrolyte transport. Electrophysiological
studies using the short-circuit current technique demonstrated a stimulatory effect of basolaterally applied ANG
II on the epididymal electrogenic ion transport, suggesting AT1 as the target receptor (394).
III) Seminal plasma and spermatozoa. ACE enzyme
activity is low in immature animals and increases with the
onset of sexual maturity (126, 314). The ACE activity in
semen is enhanced by sexual stimulation (282, 313) but is
normal in oligospermic men (281). A role of the tACE in
capacitation has been suggested by several authors (211,
658). Previous reports have suggested that ACE is released during sperm capacitation (356), which was confirmed after exposure to ACE inhibition that affected the
acrosome reaction and the ability of human sperm to
penetrate an egg (212).
Knockout technology was used to investigate the role
of ACE in male fertility (361). Hagaman et al. (246) have
shown with this method that although male mice lacking
ACE were infertile, the number of sperm, the viability,
motility, capacitation, and induction of the acrosome reaction were normal. Despite these normal functional parameters, very few sperm are found in the uterine tube
region, and even those sperm that reach the oviductal
ampulla are less likely than normal sperm to fertilize eggs
because of their reduced capacity for zone binding. The
authors suggested that tACE may play a role for the
detachment of sperm from the oviduct epithelium and/or
other structures in the female reproductive tract at capacitation. Esther et al. (189) used targeted homologous recombination to introduce a modified ACE allele into a
mouse line. Homozygous male mice have markedly reduced blood pressure, severe renal disease, and reduced
fertility, however, corresponding to no defect in sperm
number, morphology, or motility. Corresponding to this,
Ramaraj et al. (567) used transgenic techniques to gener-
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mal smooth muscle, and the density of ANG II binding
sites was markedly reduced in benign prostatic hyperplasia. It has been suggested that this may be due to receptor
hyperstimulation by increased local levels of ANG II in
benign prostatic hyperplasia.
F) VAS DEFERENS. I) ACE. Immunohistochemistry
showed strong staining for somatic ACE in cells of the vas
deferens in both young and adult rabbit (45), whereas
other authors could only describe low ACE activity (735).
G) SEMINAL VESICLES. I) ACE. Only low ACE activity was
found in seminal vesicles (735).
H) FUNCTION. I) Testis. After hypophysectomy renin levels in the rat testis decreased significantly, whereas
plasma renin was slightly increased (480), suggesting an
alternate regulation of the circulatory and testicular RAS.
The immunohistochemical renin staining of rat Leydig
cells was suppressed or abolished by hypophysectomy
and estrogen treatment and was reduced by gonadotrophin stimulation (520, 525). The treatment of cultured
mouse Leydig tumor cell line with human chorionic gonadotropin or bovine luteinizing hormone results in a high
increase of renin activity (521). It has to be noted in this
context that almost all renin activity is confined inside the
cell with only 1–2% of its total activity being present in the
culture medium. Okuyama et al. (514) have shown that
treatment with hCG increases the plasma renin activity in
internal spermatic vein without an increasing of the systemic plasma renin activity. The authors could not observe any release of renin from Leydig cells into testicular
blood flow under basal conditions.
There is a positive correlation between testosterone
and plasma renin activity in the internal spermatic vein of
humans after hCG treatment (525).
Treatment with hCG or bovine luteinizing hormone
increased also the ANG production in a cultured mouse
Leydig tumor cell line (521). It is noteworthy that the
major portion of ANG II is released in the culture medium
and the majority of ANG I was present in the cell. Together with the mentioned intracellular presence of renin
and ACE (523), this supports the possibility of intracellular formation of ANG II.
Hirai et al. (275) could verify that the AT1 and AT2
mRNA gene expression in rat testis is pituitary dependent.
After hypophysectomy, the receptor gene expression was
significantly increased. Human chorionic gonadotrophin
and human menopausal gonadotrophin reduced the AT1
and AT2 mRNA gene expression. Furthermore, the AT2
mRNA expression in rat testis is dependent on developmental stages, since Northern blot analysis showed that
mRNA expression of both AT1 and AT2 types decreased
with age (334). Aguilera et al. (7) reported also a decrease
in ANG II binding during development and that in immature rat a high proportion of ANG II receptors in the testes
are located in nondifferentiated mesenchymal cells of the
interstitium. Hypophysectomy led to a marked increase in
PHYSIOLOGY OF LOCAL RENIN-ANGIOTENSIN SYSTEMS
E. Skin
1. Renin
Northern blot analysis showed renin mRNA expression in murine subcutaneous tissue but not in murine
dermis and epidermis (653).
2. ACE
One study (685) could detect large amounts of ACE
in subcutaneous tissue of the rat by quantitative autoradiography, but it is unclear which cell type expresses ACE
in this tissue. It could also be expressed by vascular
endothelial cells or be taken up from the circulation. No
signal for ACE was detected in the dermal and epidermal
layers of rat skin. Steckelings and co-workers (675)
pointed out that the absence of ACE in this region as well
as in the subcutaneous tissue may not present a problem
for local ANG formation, since the skin is abundant in
mast cells and that mast cell-derived chymase may act as
a substitute for ACE (217, 675). Moreover, more recently,
it was shown that mast cells are an additional source of
renin synthesis (654), which could be of relevance for the
RAS activity and regulation at the tissue level, because of
the ubiquity of mast cells in tissues.
3. Angiotensinogen, ANG I, and ANG II
There is only one study suggesting local production
of ANG I and ANG II in the skin of captopril-treated pigs
(130). ANG I and ANG II levels in the presence of constant
intracardiac infusion of 125I-ANG I and 125I-ANG II were
measured in arterial and venous plasma across cutaneous
Physiol Rev • VOL
vascular beds, and these values were compared with
plasma renin activity. The data provide a higher level of
ANG I in venous plasma compared with the level in
arterial plasma, independent of plasma renin activity. This
is seen as evidence for local ANG I release; however, the
concentration difference could also be caused by a higher
local renin activity. Unfortunately, there are no data available that could be considered as evidence for the local
synthesis of angiotensinogen.
4. Angiotensin receptors
Radioligand binding studies were performed on cultured human primary keratinocytes and showed binding
to ANG II. Interestingly, the AT1 and AT2 receptor antagonists losartan and PD123177 are not able to displace the
radioligand. Thus the keratinocytes seem to express an
ANG II receptor subtype distinct from AT1 and AT2 receptors (673).
5. Function
A) WOUND HEALING AND REPAIR. Increased ANG II levels
were measured during wound healing in rat skin (243,
345), but this is not conclusive evidence for local production because ANG II could also be taken up from plasma
into the tissue. Previous studies described a proliferative
and antiproliferative effect of ANG II in the skin which
appear to be mediated by AT1, AT2, and non-AT1, non-AT2
receptors (105, 485, 524, 673, 681).
Quantitative autoradiography demonstrated that the
expression of ANG II receptors was significantly enhanced during experimental wound healing. Young rat
skin normally contains mainly AT1 receptors, but during
experimental wound healing a selective and localized increase in expression of AT2 receptors occurs (745). This
study suggested skin fibroblasts as the primary target
cells for ANG II. Other investigators (345) have found
significant decreases in the number of AT1 receptors and
a modest but not statistically significant appearance of
AT2 receptors in adult rat skin during wound healing. This
is not necessarily a contradiction and could be an indication for the importance of the proportion or balance of
these two receptors. Abiko et al. (3) have shown that an
immediate and transient reduction in ANG II receptor
expression occurred after wounding rat skin, followed by
an increase in the number of the receptors that was
maintained for 5–7 days, and that the receptors were
predominantly of the AT1 receptor subtype. In a cutaneous repair model, Sun et al. (686) have shown that the
appearance of myofibroblasts is associated with ANG II
generation which regulates fibrogenesis by AT1 receptor
binding. In rat skin slices, ANG II binding to AT1 receptors
increases inositol phosphate production, while binding to
AT2 decreases inositol phosphate production; thus both
receptors play opposite roles (243). It has to be noted that
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ate mice with exclusive expression of tACE using ACE
knockout mice as a background. These animals express
ACE only in sperm, since a sperm-specific promoter was
used to direct expression of tACE. The background ACE
knockout mice lack both isoenzymes (somatic ACE and
tACE) and exhibit low blood pressure, kidney dysfunction, as well as male infertility. The transgenic “rescue” by
the selective tACE overexpression resulted in normalized
fertility. The male fertility defect does not appear to be
related to the low levels of ANG II expected in the ACEdeficient mouse. Angiotensinogen-deficient mice, which
cannot synthesize ANG II, do not have any defects in male
fertility (246, 339). Nagata et al. (477) have also investigated a mouse line lacking angiotensinogen and suggested that female-derived ANG I is also not an essential
substrate for tACE.
There are suggestions for a function of AT1 receptors
as determinants of sperm motility, since ANG II increases
both the percentage of motile sperm and their linear
velocity and AT1 receptor antagonists inhibit this action
of ANG II (743).
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MARTIN PAUL, ALI POYAN MEHR, AND REINHOLD KREUTZ
it was unclear in the two former studies in which cell type
the ANG II receptor regulation and signal transduction
occurred (243, 686). Further investigation has suggested a
mitogenic effect of ANG II of keratinocytes via a non-AT1,
non-AT2 ANG receptor (673). ANG-(1O7) binding sites
were also characterized in human skin fibroblasts (493).
2. Pancreas
3. Stomach
A) RENIN. Renin mRNA was detected in the connective
tissue surrounding the blood vessels and in reticular fibers
A) ANGIOTENSINOGEN, ANG I, AND ANG II. Angiotensinogen
mRNA was found in rat stomach (74). Ludtke et al. (422)
F. Digestive Organs
1. Salivary glands
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A) RENIN. The salivary gland of some mouse strains
expresses significant amounts of renin. It is interesting to
note that renin production in the salivary gland is particularly high in mouse strains that contain two renin genes
(Ren-1 and Ren-2), which are the result of a gene duplication that occurred during evolution (2). Both genes are
expressed in most mouse organs such as kidney (204),
whereas only Ren-2 is expressed in mouse salivary
glands, particularly in the submandibular gland (179, 205).
Although the functional significance of this gene duplication is unknown, the study of two-gene mice provided an
excellent opportunity to investigate the molecular basis
of tissue-specific renin gene expression, and the functional role of the Ren-2 gene has been studied extensively
in transfected cells (529), transgenic mice (472), and
transgenic rats (471). The latter model is of particular
importance in this context, since the transgenic rats with
Ren-2 expression suffer from fulminant hypertension and
severe end-organ damage. The gene duplication is specific
for the mouse, and expression of the rat and human renin
genes correlates (159) with that of the mouse Ren-1 gene.
B) ANGIOTENSINOGEN. Low angiotensinogen mRNA levels
were detected in the CD-1 male mouse and the C57BL/6
mouse (701) submandibular gland, but like renin mRNA,
angiotensinogen mRNA could not be detected in rat submandibular gland (174).
C) RECEPTORS. Using a radioligand binding assay, Matsubara et al. (442) found mainly AT1 receptor subtypes in
rat submandibular organ.
D) FUNCTION. The ultimate role of renin and other components of the RAS in the submandibular gland are not
known. It has been associated with mediation of the “fight
and flight” reaction. Renin activity in the salivary glands
increases with stress, pituitary hormone release, and adrenergic stimuli and is associated with aggressive behavior in mice (557, 775). There have also been indications of
a role in saliva production, since ACE inhibition increases
overall saliva secretion of humans but does not affect its
composition (483).
within the islets of human pancreas (695). Renin protein was
found in the beta cells of the human islets of Langerhans and
in endothelial cells of the pancreatic vasculature.
B) ANGIOTENSINOGEN, ANG I, AND ANG II. Angiotensinogen
mRNA and angiotensinogen protein were found in canine
pancreas (93). In contrast, Campbell and Habener (74) did
not find angiotensinogen mRNA in rat pancreas. The presence of ANG II was reported in canine pancreas by Chappell et al. (93). Also in mouse ANG II-like immunoreactivity was localized predominantly in the endothelial cells of
pancreatic blood vessels and the epithelial cells of pancreatic ducts from a subgroup of the vessels and ducts,
and with lower intensity in acinar cells and in smooth
muscle layers overlying the pancreatic ducts and blood
vessels. However, no ANG II immunoreactivity was detected in the islet cells (395).
C) ANGIOTENSIN RECEPTORS. The majority of ANG II binding
sites in the canine pancreas could be classified as AT2 subtypes, although AT2 subtype was also detected (92). The
same study has reported that the binding sites were localized over islet cells, acinar and duct cells, as well as the
pancreatic vasculature. ANG II binding sites were also found
in islet cell membranes and the exocrine pancreas of the rat
(224). Another study has reported predominant distribution
of AT1 and AT2 receptor subtypes in the endothelia of the
blood vessels and the epithelia of the pancreatic ductal
system of rat and mouse (393). The presence of the AT2
receptor in the beta cells of the human islets of Langerhans,
and in endothelial cells of the pancreatic vasculature, was
demonstrated by Tahmasebi et al. (695).
D) FUNCTION. The pancreatic RAS appears to regulate
secretion of pancreatic hormones. Elevated plasma sodium concentration resulted in depression of the binding
affinity and capacity, whereas sodium depletion elevated
both binding affinity and capacity of ANG II binding sites
in rat pancreas (224). In a rat pancreatic acinar cell line
(AR4 –2J), ANG II stimulated via AT1 receptor a dosedependent release of amylase (97).
In rat pancreas, chronic hypoxia caused a marked
increase in angiotensinogen both at the protein and gene
levels and an increase in AT1B and AT2 receptor mRNA
when compared with that in the normoxic pancreas (91).
ANG II infusion induced a dose-dependent reduction
in both whole pancreatic and islet blood flow in rats and
points to a pivotal role of islet blood perfusion for an
adequate insulin release (79). More recent studies suggest
a role for ANG II-induced apoptosis of pancreatic acinar
cells in pancreas fibrosis mediated by AT1 receptors
(763). This finding and the overall functional relevance of
the tissue RAS in the pancreas awaits further study (396).
PHYSIOLOGY OF LOCAL RENIN-ANGIOTENSIN SYSTEMS
have reported phasic and/or tonic responses of human
gastric smooth muscle to ANG II which often exceeded
the maximum acetylcholine-induced activation.
B) FUNCTION. Cullen et al. (123) have found that captopril alleviated the systemic acidosis and the stress ulceration produced by canine hemorrhagic shock. Because
during shock captopril enhanced blood flow to the small
intestine, pancreas, liver, and spleen, but not to the stomach, the authors concluded that alleviating systemic acidosis was mediated through enhanced perfusion of other
visceral organs.
4. Intestine
ANG pathways in the intestinal tract are represented
in Figure 6.
A) RENIN. Renin gene expression was found in the intestine of human and mouse (636).
B) ACE. ACE has been localized in the brush border of
human jejunum (678). In the rat, the highest ACE mRNA,
ACE protein, and activity within the intestine were found
in the brush-border membrane fraction in the proximal to
midregion of the small intestine (186, 806). ACE activity
was highly enriched on both the intestinal vascular
Physiol Rev • VOL
plasma membrane and the intestinal brush border of the
rat (764). ACE immunoreactivity was detected in human
small intestine blood vessels (microvascular endothelium
was strongly labeled) and the absorptive epithelial cells of
intestinal mucosa, especially in microvilli and brush borders (62). Costerousse et al. (110) reported that in the rat
intestine, ACE mRNA levels and ACE activity were very
high at birth and then decreased dramatically during the
next 2 wk. ACE activity was reported also in the brushborder membrane from the small intestinal epithelium of
the common grackle (679). ACE2 mRNA expression is
ubiquitously found including the intestine (251); however,
systematic expression analysis revealed a remarkable surface expression of ACE2 protein in enterocytes of the
small intestine (251).
C) ANGIOTENSINOGEN. Angiotensinogen mRNA was detected in mesentery but not in small intestine of rat (74).
D) ANGIOTENSIN RECEPTORS. AT2 receptor mRNA and protein were characterized on cultured rat intestinal epithelial cells (661). The distribution of ANG II receptor was
localized by Duggan et al. (171) via in vitro autoradiography. ANG II receptors were most abundant in the colon,
followed by the ileum, duodenum, and jejunum. Within
each segment of the intestine, specific ANG II binding
sites were localized exclusively to the muscle layer. Sechi
et al. (633) detected by autoradiography AT1 and to a
lesser extent AT2 receptors in rat intestine. Specific binding was moderately abundant in the mucosa and the
muscularis of both jejunum and ileum, whereas no binding was present in the submucosa and the serosa. In the
colon, binding was significantly more abundant in the
muscularis than in the mucosa. Hosoda et al. (288) could
clearly demonstrate the distribution of AT1 immunopositive cells in enteric nerves and moderately in surface
epithelial cells of guinea pig distal colon. Functional AT1
receptors were shown by Schinke et al. (618) in the rat
ileum and duodenum
E) FUNCTION. At low physiological doses, ANG II stimulates jejunal sodium and water absorption in adrenalectomized rats, whereas at a high dose the peptide inhibited
absorption (400). However, the stimulation of jejunal water absorption was abolished in peripherally sympathectomized rats (400). In vitro study showed that mucosal
additions of ANG II were more or less able to stimulate
jejunal sodium and water absorption than serosal addition (399). Also, ANG III is able to stimulate rat jejunal
fluid absorption. This effect can be blocked by guanethidine, phentolamine, and prazosin, suggesting that ANG
III-increased intestinal absorption is secondary to the release of norepinephrine from sympathetic nerves in the
jejunum (398). The same author has reported in another
study that ANG II was able to enhance absorption in
isolated rat jejunum in the presence of prazosin (399).
This is contradictory to the hypothesis of involvement of
the sympathetic nervous system in mediating ANG II-
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FIG. 6. RAS in the intestinal tract. Interaction with plasma RAS and
RAS in nerve endings.
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Physiol Rev • VOL
inducing peristaltic waves. In the ileum, the contraction is
caused by the longitudinal smooth muscle and is mediated by the AT1 receptor.
Jaszewski et al. (317) have reported that mucosal
levels of ANG I and II were elevated in patients with
Crohn’s colitis versus normal subjects and other forms of
colitis and that mucosal levels of ANG I and ANG II
correlated well with the degree of macroscopic inflammation in Crohn’s disease.
The RAS is highly activated during hyovolemic shock
and has been suggested to be involved in the pathophysiology of the markedly deteriorated splanchnic circulation seen in this condition. Aneman et al. (16) detected
that the downregulation of mesenteric oxygenation and
duodenal mucosal function during hypovolemia in pigs
can be prevented by administration of enalaprilat,
whereas guanethidine is ineffective in this respect. The
authors concluded that this might be of clinical interest to
support mesenteric perfusion and organ function in hypovolemia (16). Also, AT1 receptor blockage ameliorated
mesenteric and particularly jejunal mucosal hypoperfusion during hypovolemia in pigs (17). Furthermore, mortality in conjunction with acute hypovolemia and retransfusion could be completely avoided. Oldner et al. (517)
reported that ANG II receptor antagonism increases gut
oxygen delivery but fails to improve intestinal mucosal
acidosis in porcine endotoxin shock. Tadros et al. (694)
detected that ANG II appears to play a pivotal role in the
burn- and endotoxin-induced intestinal ischemia and
reperfusion injury in pigs, with subsequent increases in
permeability and bacterial translocation and that administration of the ANG II receptor antagonist DuP753 after
birth significantly reduces the extent of these events.
5. Colon
A) ANGIOTENSINOGEN. Angiotensinogen mRNA was detected in rat large intestine (74).
B) FUNCTION. It has been demonstrated that ANG II
stimulated fluid transfer and sodium transport in segments of isolated rat proximal colon. Further investigation suggested that ANG II stimulated a coupled NaCl
transport (145). In rat distal colon, ANG II can stimulate
intestinal water transport via an electroneutral mechanism already at subpressor doses; this is a specific effect
and in contrast to aldosterone which stimulates intestinal
sodium and water transport by electrogenic mechanisms
(402) involving the epithelial sodium channel (47).
G. Sensory Organs
1. Eye
The presence of a local RAS in the eye has been
suggested by studies demonstrating the expression of all
components of the system in ocular tissue. Wagner et al.
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stimulated fluid absorption. Cox et al. (116) have shown
that ANG II, if applied to the basolateral surface, elicited
increases in short-circuit current in preparations of rat
jejunum and decreases in the descending colon. They
have further shown that the response was not affected by
␣- or ␤-adrenoceptor antagonists but by a chloride channel blocker and that the increase/reduction in short-circuit current elicited by ANG II in jejunum/colon was
inhibited by both piroxicam and indomethacin. Jin et al.
(320) detected that in rat jejunum the low-dose ANG
II-stimulated fluid and sodium absorption was blocked
completely by the specific AT2 receptor antagonist
PD123319 but was unchanged by losartan. Conversely,
high-dose ANG II inhibition of absorption was blocked by
losartan but not by PD123319. The ANG II-mediated sodium and fluid absorption involved cGMP formation, and
the high-dose inhibition via the AT1 receptor is both negatively coupled to cAMP and increases jejunal PGE2 production. A comparison between SHR rats and normotensive controls has shown that SHR possess an enhanced
intestinal fluid absorption both in hypertensive adults and
in normotensive young SHR (170). ANG II was also able to
enhance water absorption and antagonized the secretory
effect of vasoactive intestinal polypeptide (VIP) in the
ileum similar to norepinephrine (49). The increased rat
jejunal fluid absorption after extracellular fluid reduction
is not affected by adrenalectomy, but is abolished by
nephrectomy, captopril, prazosin, and peripheral sympathectomy, suggesting that ANG II is generated after extracellular fluid reduction and increases jejunal fluid absorption by facilitating the release of norepinephrine from
enteric sympathetic nerves (78, 399, 400). Serosal addition
of ANG II produced a concentration-dependent shortcircuit current in guinea pig distal colon (288). The authors reported that the ANG II evoked responses were
mainly due to Cl⫺ secretion and mediated by the AT1
receptor. Hatch et al. (263) reported that the enhanced K⫹
secretion in distal colon of rats with chronic renal failure
was mediated by AT1 receptors, since the secretion was
reversed to an absorptive flux by losartan treatment, and
rats with chronic renal failure exhibit twofold higher ANG
II binding sites in distal colon compared with controls.
Yoshioka and co-workers (805, 806) detected that the
peptidase activity of the rat brush-border membrane for
specific peptide sequences can be inhibited by ACE inhibition. The authors suggested that intestinal brush-border
membrane ACE functions as a digestive peptidase. This
group also suggested (186) that ACE is an important
intestinal dipeptidyl carboxypeptidase, participating in
the digestion and assimilation of dietary peptides in rats
(186). Suzuki et al. (690) detected that a diet high in
proline is particularly effective in increasing intestinal
ACE mRNA and activity in rats.
ANG II causes a contractile response in the rat ileum
but not in the duodenum (617), pointing to a role in
PHYSIOLOGY OF LOCAL RENIN-ANGIOTENSIN SYSTEMS
2. Cochlea
There are suggestions of an influence of ANG II on
cochlear blood flow, which very well could be a secondary effect. Wright et al. (784) exposed guinea pigs to a
120-dB white noise for 30 min. The result was a fourfold
elevation in plasma concentration of ANG II. A second
experiment in the same study showed that an intra-arterial injection of ANG II (at concentrations comparable to
those measured after noise exposure) increases the systemic blood pressure and cochlear blood flow. This finding suggests that elevated blood pressure, caused by noise
exposure and mediated by ANG II, increases the cochlear
blood flow, and it was suggested that this is due to a lack
of a cochlear blood-pressure autoregulation in guinea
pigs. Kawakami et al. (337) showed that cochlear blood
flow of guinea pigs may have some autoregulation but was
Physiol Rev • VOL
less than brain blood flow. Unlike this finding, Quirk et al.
(563) have found a cochlea blood-flow autoregulation in
rats mediated directly by ANG II. Intra-arterially infused
ANG II produced an initial increase in cochlear blood flow
that is followed by a slow steady return to baseline,
despite sustained elevations in systemic blood pressure.
Furthermore, a direct infusion of ANG II in the anterior
inferior cerebellar artery of rats (563) results in significant
reduction in cochlear blood flow without changes in systemic blood pressure. This effect can be abolished by
ANG II receptor antagonism. Another study (107) investigated the role of ANG IV in the cochlear blood flow in
guinea pigs. Anterior inferior cerebellary artery infusion
of ANG IV increased in a dose-dependent manner the
cochlear blood flow with little change in mean arterial
blood pressure.
The role of ANG II in cochlear blood flow, however,
appears to be species specific and is not completely understood. This notion is based on results from an investigation that has shown that ICV-administered ANG II
leads to blood pressure elevation and that cochlear blood
flow was more highly correlated with blood pressure in
the guinea pig than in the rat in this setting (209).
A pathophysiologically oriented explanation of the
controversy has been offered by Goldwin et al. (236). The
discovery that during noise exposure insufficiencies in
cochlear blood flow may cause temporary or permanent
threshold shifts suggests that vasoactive substances including ANG II may mediate this effect. By pretreatment
with ANG II receptor antagonists, both cochlear microcirculation and auditory sensitivity were measured during
noise exposure. Results showed that pretreatment prevented this noise-induced microcirculatory ischemia and
preserved auditory sensitivity at the low frequencies
tested (236). In summary, the evidence for the existence
of a local cochlear RAS is scarce and needs further analysis. Moreover, it is not at all clear whether local production of ANG II in the cochlea plays a significant role for
the effects reported so far.
H. Lymphatic Tissue
1. White blood cells
A) MONOCYTES. I) Renin. Renin mRNA was detected in
rat peritoneal macrophage/monocyte cells (308). Also,
renin-like immunoreactivity was detected within these
cells by the same authors, suggesting that monocytes may
be a source of tissue renin in some pathological conditions. Dezso et al. (157) detected renin protein in rat and
mice alveolar macrophages and monocytes by high-pressure liquid chromatography.
II) ACE. ACE mRNA was found in human monocytes, but only after 4 days in culture (23). Prominent
staining for ANG II was found in human mononuclear
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(752) have demonstrated that the mRNA of renin is expressed in the retinal epithelium, whereas angiotensinogen and ACE mRNA were found both in the retinal epithelium as well as in the neural retina of the eye. These
data suggest that the machinery for ANG production is
present locally and not only restricted to vascular structures in the eye. Evidence that the RAS is also expressed
at the protein level has been provided by Sramek et al.
(670, 671) who used immunohistochemistry against prorenin and angiotensinogen to describe prorenin in the
ciliary body and angiotensinogen in the pigmented ciliary
epithelium.
The question of whether the presence of the RAS
components also leads to local production of ANG peptides has been answered by Danser et al. (131) who
suggested that the ocular ANG concentrations are too
high to be caused by blood-borne peptides.
A) FUNCTION. Whereas the presence of the components
of the RAS has been well documented in the eye, little is
known about its local function. Since ANG II receptors
have been detected primarily on retinal blood vessels, it
has been suggested that the ocular RAS may be involved
in the regulation of ocular vascular tone. Apart from this
aspect, the ocular RAS may be involved in the regulation
of aqueous fluid since local application of ACE inhibitors
influences aqueous fluid production. A recent report suggested that the ocular RAS may be relevant for maintaining normal secretory function of epithelial cells in the
ciliary bodies (125). In this study, ANG II was defined as
a secretagogue, leading to cell volume loss in cultured
nonpigmented epithelial cells derived from human ciliary
body. This process is antagonized by losartan, suggesting
that ANG receptor blockade could be a new pharmacotherapeutic approach in the treatment of glaucoma. The
pathophysiological role of the local RAS in the eye appears of special clinical importance since it has been
linked to diabetic mellitus (682).
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MARTIN PAUL, ALI POYAN MEHR, AND REINHOLD KREUTZ
2. Spleen
A) RENIN. With the use of RNase protection assays, renin
mRNA was detected in rat spleen. Ekker et al. (179) have
also found renin gene expression in rat and mouse spleen by
primer-directed enzymatic amplification of cDNAs.
B) ANGIOTENSINOGEN. Angiotensinogen mRNA was detected in rat spleen (74).
C) ANGIOTENSIN RECEPTORS. Binding sites for ANG II were
localized in the red pulp of the spleen of rats and mice by
quantitative autoradiography (86). ANG II binding sites
were also localized on isolated rat spleen cells. Tsutsumi
et al. (722) showed that the binding sites for ANG II are
attributable to the AT1 receptor subtype. However, mouse
spleen lymphocytes seem to posses both AT1 and AT1
receptor subtypes (368).
3
D) FUNCTION. ANG II significantly enhanced the [ H]thymidine incorporation into DNA of mouse splenocytes
(368). The stimulatory effect was only blocked when losartan or PD123319 was added together with ANG II.
B) ANGIOTENSIN RECEPTORS. ANG II receptors were not
detected in thymus sections from rats or mice, or on
isolated rat thymocytes (86). But in newborn rats, Correa
et al. (108) have detected AT1/AT2 receptors (15%/85%) in
the trabecula. The binding sites were no longer detected
in 4- and 8-wk-old rats.
I. Adipose Tissue
Apart from its presence in white adipose tissue
where the local RAS may play a role in the pathogenesis
of syndrome X, RAS components have also been detected
in brown adipose tissue located adjacent to the adventitia
of blood vessels, where it could provide an interface with
the vascular RAS.
1. Renin
Renin mRNA was found in adipose tissue of obese
humans (335). Renin activity was localized in interscapular brown adipose tissue, especially in adipocytes, which
is not decreased after bilateral nephrectomy (643). Renin
and all other components (angiotensinogen, renin binding
protein, ACE, and AT1 receptors) that are necessary to
form a local RAS were found in human preadipocytes
(620), in human adipose tissue, and in cultured human
adipocytes (183, 184).
2. ACE
ACE mRNA was found in both human subcutaneous
and extraperitoneal adipose tissue, especially in adipocytes (328). Also, Karlsson et al. (335) have detected ACE
mRNA in adipose tissue of obese humans. ACE synthesis
at protein levels was detected in human preadipocytes
(620).
3. Angiotensinogen, ANG I, and ANG II
Angiotensinogen mRNA was identified in periatrial
and periaortic brown adipocytes and in fibroblast-like
cells of periaortic connective tissue and mesentery of rat
(73, 84). By Northern blot analysis, Karlsson et al. (335)
demonstrated angiotensinogen gene expression in adipose tissue from adipose humans. Slices from interscapular brown adipose tissue are able to release immunoreactive ANG II peptides (643). Schling et al. (620) showed
that ANG II was secreted both by undifferentiated human
preadipocytes and immature adipocytes, and its production was significantly elevated in differentiated cells.
3. Thymus
4. Angiotensin receptors
A) RENIN. Renin gene expression was found in rat and
mouse thymus by primer-directed enzymatic amplification of cDNAs (179).
The receptor subtype that is present most abundantly
in both white and brown adipose tissue is the AT1 receptor subtype. Mice adipose tissue expresses predominantly
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leukocytes (348). These authors have also detected ANG
I staining, but the signal was less pronounced than for
ANG II. Rat and mouse macrophages and monocytes
contain ANG I and ANG II as well (156).
III) Angiotensin receptors. Shimada and Yazaki
(647) demonstrated ANG II binding sites in human mononuclear leukocytes via autoradiography. ANG II binding
sites were reported on guinea pig macrophages (708),
which were found responsible for ANG II incorporation
by these cells. Finally, Simon et al. (657) reported that
ANG II binding to human mononuclear cell is not easily
reversible and is poorly inhibited in a competitive manner, suggesting that endocytosis occurs.
Kim et al. (340) reported that ANG II increases monocyte binding to human as well as rabbit aortic endothelial
cells, suggesting a role in arteriosclerosis.
B) GRANULOCYTES. Human neutrophils possess the ability
to convert ANG I to ANG II via cathepsin G, a lysosomal
serine protease (349). Reilly et al. (571) reported a rapid
conversion of ANG I to ANG II by human neutrophil
cathepsin G and human skin mast cell chymase. And
Wintroub et al. (780) demonstrated that angiotensinogen
is also cleaved by cathepsin G, suggesting that a human
granulocyte-angiotensin system does not require renin or
ACE. Human polymorphonuclear leukocytes showed very
little staining for ANG II (348), whereas ANG II can induce
neutrophil chemoattractant release from human and bovine cultured endothelial cells (191) pointing at local
regulation.
PHYSIOLOGY OF LOCAL RENIN-ANGIOTENSIN SYSTEMS
AT1A subtypes (68). Crandall et al. (121) localized AT1
receptor protein in rat epididymal, mesenteric, and retroperitoneal adipose tissue and human omental and subcutaneous adipose tissue. It is also notable that in human
preadipocytes there was a high-affinity ANG II binding
site of the AT1 subtype (121). Rat white adipose tissue
contained a greater number of ANG II binding sites than
brown adipose tissue and both present the AT1 subtype
(83).
5. Function
Physiol Rev • VOL
blood pressures as a background, the scientists generated
transgenic mice with angiotensinogen expression restricted to adipose tissue. The animals showed circulating
angiotensinogen, increased fat mass, normotension, and
restored renal function (438). In addition, transgenic mice
derived from wild-type mice and designed to overexpress
angiotensinogen only in adipose tissue demonstrated elevated plasma angiotensinogen and developed hypertension (438). In another study, the authors could demonstrate by studying angiotensinogen-deficient and wildtype mice that angiotensinogen appears to be involved in
the regulation of fat mass through a combination of decreased lipogenesis and increased locomotor activity that
may be centrally mediated (439). ANG II has been shown
to be able to induce leptin expression in adipocytes (344),
and Cassis et al. (82) suggested that in contrast to systemic ANG II, only locally produced ANG II is able to
elevate plasma leptin levels, since systemic ANG II also
leads to sympathetic activation, which would diminish the
effect of ANG II.
III. PRENATAL DEVELOPMENT
Local ANG formation and tissue-specific effects of
ANG peptides on growth and differentiation are thought
to be extremely important for embryonic and fetal development. There appears to be a close interaction between
plasma and tissue RAS in this situation.
1. Renin
Newborn rat plasma renin activity and plasma renin
concentration are higher than adult levels (551, 755). In
the rabbit fetus, plasma renin activity shows very low
values but increases rapidly during the last 4 days of
gestation and reaches a maximal level in the early postnatal period. Siegel and Fisher (651) have shown that
furosemide-induced plasma renin activity was for the first
time inducible at 106 days of gestation and increased with
the gestational age in the fetal lamb and that the fetal
lamb plasma aldosterone level did not increase in response to endogenous renin stimulation.
2. ACE
Rat somatic ACE is first identifiable at 18 days of
gestation and increases thereafter until 2– 6 wk postpartum (656, 753, 754). In addition, in the human fetal lung,
ACE activity increased with gestation and reaches its
mature activity earlier than those in the rat (656). Plasma
ACE correlated with gestational age of fetal lambs and
was associated with prepartum increases in plasma cortisol and blood pressure; by 2 wk of postnatal age, plasma
ACE had decreased to the value seen in nonpregnant
adult ewes. The maternal plasma ACE was similar at all
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ANG II plays a role in sympathetic nervous systemmediated thermogenesis. Cold exposure resulted in an
increase in interscapular fat ANG II content, without concomitant changes in plasma components of the RAS, and
led to an ANG II-mediated presynaptic facilitation of
evoked norepinephrine overflow from rat interscapular
fat during cold exposure that can be diminished by losartan (80). Cold exposure induced an increase of ANG II in
brown adipose tissue without detectable changes in
plasma components of the RAS and mediated facilitation
of sympathetic neurotransmission (80, 81).
Treatment of cultured human preadipocytes with
ANG II resulted in an AT1 receptor-mediated increase of
expression of the mRNA for cell cycle regulatory protein
cyclin D1 (120). The role of ANG II in adipose cell maturation and growth was also supported by a study that
showed the differences in angiotensinogen mRNA and
protein content between young and adult rats (258). Angiotensinogen mRNA (protein) was approximately twofold (3-fold) higher in adipocytes of young (8 wk) rats
compared with old ones (26 wk). Interestingly, Brink et al.
(60) have found that ANG II infusion to rats caused many
systemic changes like decreasing skeletal muscle mass or
increasing left ventricular weight, but fat tissue was unchanged.
Safonova et al. (588) showed that angiotensinogen
gene expression in adipocytes is activated by fatty acid
levels in a dose-dependent manner. Jones et al. (327)
showed that ANG II significantly increased triglyceride
content and the activities of two key lipogenic enzymes
(fatty acid synthase and glycerol-3-phosphate dehydrogenase) in 3T3-L1 and human adipose cells. Interestingly,
this effect was mediated by the AT2 receptor, in contrast
to other publications that predominantly or exclusively
detected AT1 receptors (68, 121, 327). Body weight correlated positively with adipose angiotensinogen mRNA expression in humans (226, 732). Kouyama et al. (360) have
shown that mice lacking AT1A receptor have higher energy expenditure and thus show attenuation of diet-induced weight gain and adiposity. A role of angiotensinogen, derived from adipose tissue, in blood pressure regulation and adipose tissue volume has been postulated
(438). Using angiotensinogen-deficient mice with reduced
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MARTIN PAUL, ALI POYAN MEHR, AND REINHOLD KREUTZ
gestational stages (213). Also, in fetal rabbit, an increase
of pulmonary ACE activity was detected from 22 days of
gestation until term (672).
3. Angiotensinogen
The major portion of angiotensinogen mRNA in the
embryo is most likely derived from the fetal liver, and the
level in the whole rat embryo was increasing by day 13
and reached a plateau by day 17 (380). Furthermore, the
authors suggested that the poly(A) tract of rat embryonic
angiotensinogen mRNA may be longer than that of adult
liver angiotensinogen mRNA.
The high abundance of AT2 receptors in fetal tissue
and in vitro studies suggesting the involvement of AT2
receptors in mediating programmed cell death (797) and
cell differentiation (680, 681) have lead to the hypothesis
that ANG II, acting via the AT2 receptor, is involved in
aspects of organogenesis.
5. Kidney
A) MESONEPHROS. Renin is expressed very strongly from
stage 13 in capillaries within glomeruli as well as in the
wall of arteries in the interstitium and in the arterioles up
to the aorta of the human embryonic mesonephros (630).
ACE protein can be detected by immunohistochemistry at
stage 14 in the apical membrane of the human mesonephric tubule cells. Angiotensinogen mRNA was detected by
stage 12–13 in the proximal portion of the primitive tubules of the human mesonephros. The AT1 receptor
mRNA was detected in human mesonephric glomeruli,
probably in mesangial cells, beginning at stage 12, and the
AT2 receptor mRNA was the component to be expressed
first (stage 11) and was confined to the undifferentiated
mesenchyme of the human mesonephros surrounding the
preliminary tubules and glomeruli. In addition, both the
mRNA and protein for AT1 and AT2 receptors were
present in the ovine fetal mesonephri (69).
B) METANEPHROS. The distribution of renin mRNA in human metanephros appeared slightly different from that in
the mesonephros as it had become confined to the juxtaglomerular apparatus at the vascular pole of the glomerulus and to dispersed cells of arteries located next to
glomeruli. In human metanephros, ACE activity was detected in proximal convoluted tubules and collecting
ducts in increasing amounts until birth (630). In the human metanephros, angiotensinogen mRNA showed only
weak labeling macroscopically and was expressed in
proximal tubules from 8 wk of and throughout gestation.
Hybridization signal for AT1 receptor mRNA was observed in human metanephros glomeruli and in proximal
tubular epithelium. Juxtaglomerular cells expressed AT1
mRNA as soon as they differentiated. AT2 receptor mRNA
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4. Angiotensin receptors
expression was highest in the human metanephros at 8 –9
wk gestational age. It could be detected in undifferentiated mesenchyme, surrounding tubules and immature glomeruli. The AT2 receptor mRNA signal in the human
metanephros declined after 20 wk of gestation but remained detectable until birth. Also, both mRNA and protein for AT1 and AT2 receptors were present in the ovine
fetal metanephroi (69).
A recent study (504) has indicated a positive-feedback mechanism for renin generation in cultured developing rat metanephron. Renin mRNA was localized to
developing tubules and uretral branches and glomeruli in
the cultured explants. Also, both ANG II receptors and
ANG II were detected in the rat cultured metanephroi.
After ANG II treatment, the authors detected an increase
in renin activity that was prevented by AT1 blockade,
whereas AT2 antagonism had no effect.
Maric et al. (434) have detected AT1 and AT2 receptor
binding sites by radiolabeled binding assay and AT1 and
AT2 receptor mRNA (RT-PCR) in isolated embryonic
renomedullary interstitial cells from embryonic rat kidneys. The authors have demonstrated that ANG II acts as
a potent mitogen to those cells in a time- and dosedependent manner. This effect could be abolished with
losartan but not with PD123319, suggesting that the mitogenic effect of ANG II is mediated through the AT1 receptor. ANG II was also able to inhibit growth induced by
basic fibroblast growth factor mediated by the AT2 receptor (681). Gimonet et al. (228) have shown that both ANG
II receptor subtypes are expressed early during nephrogenesis in fetal lamb but displayed specific spatial and
temporal distribution during gestation. The level of AT2
expression followed closely glomeruli proliferation rate
and disappeared after nephrogenesis completion. Also, in
the differentiated epithelial cells of macula densa, AT2
mRNA was detected. AT1 receptor was predominant in
mesangial cells of mature glomeruli but was also detected
in cells invading the inferior cleft of S-shaped bodies and
in medullar cells between tubules.
Mice lacking AT1B receptor are healthy, without an
abnormal phenotype. In contrast, Agtr1a⫺/⫺ Agtr1b⫺/⫺
mice have diminished growth, vascular thickening within
the kidney, and atrophy of the inner renal medulla (70).
The complete AT1 receptor knockout mice have no systemic response to infusions of ANG II, and the blood
pressure is reduced substantially. Interestingly, after administration of an ACE inhibitor, their blood pressure
increases paradoxically. This could be a result of interruption of AT2 receptor signaling.
Miyazaki et al. (449) have shown that AT1 receptor
knockout mice do not develop renal pelvis or ureteral
peristaltic movement. Comparing the Agtr1⫺/⫺ neonatal
mice with complete unilateral ureteral ligated wild-type
neonates, the structural anomalies were qualitatively indistinguishable between the Agtr1⫺/⫺ neonatal mice
PHYSIOLOGY OF LOCAL RENIN-ANGIOTENSIN SYSTEMS
6. Adrenal gland
Renin was detected in the cortex of adrenal gland of
mouse fetus, appearing as small patchy or granular reaction products in the perikaryon of a few cells. Later in the
gestation, numerous tiny granules were found just below
the cell membrane (358). The AT1 receptor mRNA could
be detected in the neocortex of human adrenal gland at 8
wk and throughout the gestation (neocortex differentiates into the zona glomerulosa, fasciculata, and reticularis
around the time of birth), whereas AT2 receptor mRNA is
expressed earlier (5– 6 wk) in a mass of condensed cells
above the developing kidney, namely, the future adrenal
fetal zone (630). The majority of ANG binding sites in
primary cultures of both human fetal zone and neocortex
cells were of the type 1 subtype (564). However, Breault
et al. (58) detected by autoradiographic studies that ANG
II receptors in the human fetal adrenals are mainly of the
type 2, suggesting that culture conditions increase AT1
receptor expression.
In contrast to observations in rat fetus, the adrenal
medulla of the human fetus does not express AT2 receptor
mRNA (630). In the ovine fetal adrenal gland, Wintour et
al. (779) could detect both mRNA and protein of the AT1
receptor in the zona glomerulosa and fasciculata of the
cortex, but not in the medulla by 60 days of gestation. The
mRNA of AT2 receptor was present in the same location
(and absent in the medulla) from 40 to 130 days and
declined to extremely low levels after 140 days (term is
145–150 days). The authors showed that the application of
ANG II caused a significant downregulation of the AT1
receptor mRNA expression, and the AT2 mRNA levels
remained unchanged. The adult ovine adrenal expresses
only AT1 receptor mRNA (zona glomerulosa and to a
lesser extent in the zona fasciculata, but never in the
medulla) (779).
Moritz et al. (464) showed a functional antagonistic
effect of the ANG II receptors by aldosterone secretion by
the midgestation ovine fetus. In this study, a short-term
infusion of ACTH but not ANG II stimulated aldosterone
Physiol Rev • VOL
production in the midgestation ovine fetus. However,
plasma aldosterone could be stimulated by ANG II in the
presence of a specific AT2 receptor blocker treatment,
suggesting that this may be mediated by AT2 receptors.
The AT2 receptor shows high density in the medulla
of the adult adrenal gland of rats and rabbits but is
virtually absent from the medulla of the human and bovine adrenal glands.
7. Heart
Renin mRNA could be detected in a few cells of the
human embryonic heart starting expression at stage 12
and became more abundant during the course of gestation, although the positive cells always remained isolated
and preferentially located in the inner parts of the myocardium (630). ACE activity was first detected at stage 14
in the inner layer of the human embryonic heart wall by
these authors. AT1 receptor mRNA was diffusely distributed over the human embryonic heart muscle, whereas
AT2 receptor mRNA was detected earlier, expressed at a
higher level, and located in the innermost layers of the
myocardium. By quantitative autoradiography, ANG II receptors were first detected in the rat myocardium on
embryonic day 14 and reached a maximum density within
the first postnatal week (294).
Both ANG II receptor subtypes are involved in the
regulation of type I and III collagen expression and structural protein accumulation in the developing rat heart,
since type I collagen expression in cardiac tissue was
reduced and type III collagen mRNA expression increased
in both losartan and PD123319-treated rats (371).
A moderate density of binding to ACE was first detected in the rat cardiac vasculature and heart valves on
embryonic day 19, whereas ACE was first detected in the
rat myocardium on the day of birth, with the density of
binding to ACE increasing during development (294).
More recently, a pivotal role of ACE2 for normal heart
development and function has been demonstrated for the
ACE2 homolog ACER in Drosophila (119) and for ACE2
in mice (119).
8. Vasculature
During rat aortic development, AT1 expression was
detected on gestational day 14, increased until embryonic
day 16, after which levels were similar throughout postnatal development; conversely, AT2 mRNA first appeared
at day 16, reached maximal levels between day 19 and
neonatal day 1, and decreased thereafter (295). DNA
synthesis rates decreased with aortic development, and
AT1 receptor antagonism accelerates this developmentally regulated decrease in DNA synthesis, whereas AT2
receptor antagonism blunted this decrease. Yamada et al.
(795) have also demonstrated that the expression of this
receptor mediates decline in vascular DNA synthesis that
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without surgical obstruction versus the wild-type mice
with complete unilateral ureteral ligation. In both kidneys, the calyx was enlarged and the papilla was atrophic
(449). Moreover, tubulointerstitial inflammation, e.g.,
macrophage infiltration and fibrosis, shows the same pattern. Thus the authors suggested that the abnormal kidney structure that develops in neonates during ANG inhibition is attributed largely to functional obstruction of the
urinary tract caused by the defective development of
peristaltic machinery (449). Interestingly, the irreversible
renal abnormalities that are induced by ANG II type 1
receptor blockade or ACE inhibition were attenuated by
simultaneous infusion of insulin-like growth factor I to
rats at perinatal days 3–13 (499).
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MARTIN PAUL, ALI POYAN MEHR, AND REINHOLD KREUTZ
occurs at this stage of vascular development. The AT2
receptor promotes also vascular differentiation and contributes to vasculogenesis. These authors could demonstrate that AT2 knockout mice show lower mRNA levels
for calponin in the aorta as the wild-type mouse aorta
(795). Calponin is expressed in the late stage of vascular
smooth muscle cell differentiation and correlates with
expression of the AT2 receptor. The authors have also
demonstrated that the protein levels of calponin and highmolecular-weight caldesmon were lower in the aorta of
AT2 receptor knockout mice at 2 and 4 wk after birth.
9. Liver
10. Brain
Immunostaining for ACE was observed in the developing nervous system and dermomyotome (630). Low
levels of angiotensinogen mRNA were detected in the rat
embryo head from days 17 to 19 (380). However, others
have shown that angiotensinogen mRNA was more abundant in brain than in the liver in the early gestational life
of rat embryo (soon after birth, brain angiotensinogen
mRNA levels increased to a concentration 3-fold above
fetal levels and liver angiotensinogen mRNA abundance
increased 30-fold within 12 h of birth) (333). By immunostaining, angiotensinogen was first observed on rat embryonic day 18 in the choroid plexus and ependymal cells
lining the third ventricle (474). During early postnatal
development, a rapid progression of angiotensinogen
staining appears in the astrocytes in the paraventricular
nucleus, medial preoptic area, and ventromedial and arcuate hypothalamic nuclei. Sood et al. (663) have detected angiotensinogen immunoreactivity in the hindbrain
and the spinal cord of rat fetuses. This immunoreactivity
was associated with an active cell differentiation and cell
growth. ANG II immunoreactivity was found in cells cultured from fetal rat brain of 20-day-old fetuses (770).
These cells have been identified as neurons on the basis of
morphological criteria. The AT1 receptor could be visualized in parts of the developing brain (630).
Brain AT2 mRNA was detected in many brain nuclei
in the early stage of rat prenatal development, and there
was strong but transient AT2 mRNA expression in certain
structures including the lateral hypothalamic neuroepiPhysiol Rev • VOL
11. Extraembryonic fetal tissues
A) RENIN. Renin immunoreactivity was found in the
human decidua and placenta (447). Renin mRNA and ACE
immunoreactivity were detected in the chorion, renin
mRNA in the cells of the chorionic mesenchyme, and ACE
in the epithelium of the chorion (630). The presence of
renin in human trophoblastic and amnioblastic cells was
detected via immunostaining by Poisner et al. (552, 553).
Paul et al. (532) demonstrated renin mRNA in the placenta. Renin mRNA was detectable in the human choriodecidua, whereas no renin mRNA was detected in the
intertwin chorion, chorionic basal plate, placental villae,
or amnion (299, 641). In the human choriodecidua, renin
mRNA was localized in macrophages (319) and smooth
muscle cells of veins and spiral arteries (460). Finally, the
presence of renin protein was shown by Kalenga et al.
(332). More recently, the newly high mRNA levels of the
newly identified prorenin/renin receptor were detected in
the placenta (488, 490).
B) ACE. ACE mRNA and activity in human or rat placenta were shown by several studies (332, 656, 793).
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In the human embryonic liver, hepatocytes show an
extremely high level of angiotensinogen mRNA during
formation from the foregut epithelium (630). On days
14 –15, the rat embryonic liver had reached adult morphology, and during this period, angiotensinogen mRNA
levels increased exponentially (380). Besides angiotensinogen, AT1 receptor mRNA was also expressed in
the human embryonic liver, but no expression of renin,
ACE, and AT2 receptor could be detected in the liver at
any stage of development.
thelium at day 13 of gestation; in the subthalamic and
hypoglossus nuclei at day 15; in the pedunculopontine
nucleus, cerebellum, motor facial nucleus, and the inferior olivary complex at day 17; in the thalamus, bed
nucleus of the supraoptic decussation, interstitial nucleus
of Cajal, nuclei of lateral lemniscus, locus ceruleus, and
supragenual nucleus at day 19; and in the lateral septal
and medial amygdaloid nuclei, medial geniculate body,
and the superior colliculus at day 21. The substantia nigra
and many telencephalic and medullary nuclei did not
show AT2 mRNA expression; however, AT2 is expressed
after birth in these regions (507). In nuclei involved in
motor function and sensory integration, the AT2 mRNA
expression is high and persists until brain maturity (507).
By autoradiography study, Tsutsumi and co-workers (721,
723) have detected AT1 receptor binding sites in the nucleus of the solitary tract, subfornical organ, paraventricular nucleus, and choroid plexus of fetal rat brain; AT2
binding sites were detected in the inferior olive, paratrigeminal and hypoglossal nuclei, in meninges, and cephalic soft tissues including cerebral arteries and high
ACE concentrations in choroid plexus, subfornical organ,
posterior pituitary, and cerebral arteries. Primary cultures
of astrocytes obtained from fetal rats showed ANG II
binding sites belonging only to the AT1 subtype (56).
Distinct cells (probably from neural crest) around
the neural groove and somites showed hybridization signal for AT2 receptor. During later development, the sympathetic ganglion chain showed also a strong hybridization signal for the AT2 receptor. Furthermore, all organs
that contain components of neural crest origin were labeled at stages 14 –16 (630).
PHYSIOLOGY OF LOCAL RENIN-ANGIOTENSIN SYSTEMS
of the plasma RAS as can be concluded from experiments
where nephrectomy (downregulating the formation of
ANG II in the plasma) led to upregulation or no changes
of locally formed ANG II such as in adrenal gland or brain.
In other organ systems, there appears to be close crosstalk between the local and plasma RAS. Components of
the system such as renin or angiotensinogen in the heart,
for example, may be taken up from the circulation and
stored locally to be available for local ANG synthesis and
action. In some cases, specific independent actions have
been assigned to RAS components, for example, in the
testis where a role in fertility and sperm motility is discussed.
If there is a common denominator for the physiological role of these local systems, it is the maintenance of a
balance or homeostasis at the tissue level between opposing effects mediated by the system such as growth promotion and inhibition, for example, in the heart and blood
vessels. The dual actions of ANG II on its receptors can be
considered as a basis for this balance. In addition, the
possibility of alternative pathways including the use of
different substrates such as AC-SDKP for ACE, different
receptors such as AT4, and different processing products
such as ANG-(1O7) can be responsible for mediating the
regulatory and counterregulatory effects. If this balance is
disturbed, for example, by overexpression of RAS components or inhibition of others, the RAS becomes a mediator of pathophysiological stimuli. In these regulatory
processes, the plasma RAS takes up the role of an acute
“response unit,” whereas tissue-based ANG II formation is
more linked to subacute and chronic modulation. The
concept of local or tissue-based RAS, therefore, should
not be considered as an opposing or alternative but rather
as a complimentary or integrated functional concept of
ANG formation and function. There is clearly no basis for
any controversy.
ACKNOWLEDGMENTS
We thank Doris Webb and Jessie Webb for excellent secretarial and technical support.
Address for reprint requests and other correspondence: R.
Kreutz, Institute of Clinical Pharmacology and Toxicology, Campus Benjamin Franklin, Charité-University Medicine Berlin, Hindenburgdamm 30, 12200 Berlin, Germany (e-mail: reinhold.
[email protected]).
GRANTS
This work was supported by Nationales Genomforschungsnetz Grant KGCV1, 01GS0416.
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