Physiol Rev 86: 709 –746, 2006;
doi:10.1152/physrev.00016.2005.
Hypertension, Kidney, and Transgenics:
A Fresh Perspective
LINDA J. MULLINS, MATTHEW A. BAILEY, AND JOHN J. MULLINS
Molecular Physiology Laboratory, Centre for Cardiovascular Science, Queens Medical Research Institute,
University of Edinburgh, Edinburgh, United Kingdom
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I. Introduction
II. Control of Blood Pressure by the Kidney
A. Role of the kidney in hypertension
B. Impaired renal sodium excretion as a risk for hypertension
C. Vascular-dependent hypertension
III. Additional Hypertension Risk Factors
A. Environmental
B. Ontogenic
C. Prenatal programming
D. Genetic
IV. Sodium Balance
A. Sodium transport
B. Tubuloglomerular feedback
C. TGF and the renin-angiotensin-aldosterone system
V. Evaluating Candidate Genes
A. Transgenesis by microinjection
B. Gene targeting
C. RNA interference
VI. Mendelian Hypertension
A. Mineralocorticoid hormone
B. Mineralocorticoid receptor mutations
C. Mutations altering renal transport proteins
VII. Essential or Multigenic Hypertension
A. Renin-angiotensin system
B. Natriuretic peptides and receptors
C. Endothelin system
D. Nitric oxide signaling pathways
E. Kallikrein-kinin system
F. The dopaminergic system
G. Cyclooxygenase pathway of arachidonic acid metabolism
H. Other potential contributing factors
VIII. Perspective
Mullins, Linda J., Matthew A. Bailey, and John J. Mullins. Hypertension, Kidney, and Transgenics: A Fresh
Perspective. Physiol Rev 86: 709 –746, 2006; doi:10.1152/physrev.00016.2005.—In this review, we outline the application and contribution of transgenic technology to establishing the genetic basis of blood pressure regulation and
its dysfunction. Apart from a small number of examples where high blood pressure is the result of single gene
mutation, essential hypertension is the sum of interactions between multiple environmental and genetic factors.
Candidate genes can be identified by a variety of means including linkage analysis, quantitative trait locus analysis,
association studies, and genome-wide scans. To test the validity of candidate genes, it is valuable to model
hypertension in laboratory animals. Animal models generated through selective breeding strategies are often
complex, and the underlying mechanism of hypertension is not clear. A complementary strategy has been the use
of transgenic technology. Here one gene can be selectively, tissue specifically, or developmentally overexpressed,
knocked down, or knocked out. Although resulting phenotypes may still be complicated, the underlying genetic
perturbation is a starting point for identifying interactions that lead to hypertension. We recognize that the
development and maintenance of hypertension may involve many systems including the vascular, cardiac, and
central nervous systems. However, given the central role of the kidney in normal and abnormal blood pressure
regulation, we intend to limit our review to models with a broadly renal perspective.
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0031-9333/06 $18.00 Copyright © 2006 the American Physiological Society
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I. INTRODUCTION
II. CONTROL OF BLOOD PRESSURE
BY THE KIDNEY
Long-term regulation of mean arterial blood pressure
(MABP) is intimately associated with extracellular fluid
volume (ECFV) homeostasis, which itself is determined
by sodium content. Sodium balance, i.e., the equalizing of
sodium intake by sodium output, is critical to ECFV, and
the kidneys, as the principal route through which sodium
is eliminated from the body, are therefore central to the
long-term stability of MABP. Guyton’s “renal-body fluid
feedback” hypothesis used a systems analysis approach
to demonstrate the primary importance of the kidney.
Systemic vasoconstriction could not induce sustained increases in MABP if kidney function was normal (102).
Kidney perfusion studies, exemplified in renal function
curves (Fig. 1; see Ref. 100 for review), show that a rise in
MABP (or renal perfusion pressure) is matched by increased renal excretion of sodium, or pressure natriuresis, which reduces ECFV and cardiac output, and returns
MABP to normal. (Fig. 1, point A). In other words, the
kidney strives to protect against perturbation from the
equilibrium set point, and sodium balance is thus restored
by a feedback system displaying infinite gain (101). Likewise, if MABP falls below the equilibrium point, the resulting antinatriuresis increases ECFV and MABP.
In vivo, the renal function curves can be modulated by
both neuronal and endocrine factors, one of the most powerful being the renin-angiotensin system (RAS). The role of
volume and pressure natriuresis and the impact of the RAS
on these responses have recently been reviewed (32).
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FIG. 1. Renal function curve showing the effect of mean arterial
blood pressure (MABP) on renal sodium excretion. A: the equilibrium
pressure that is maintained through adjustment in sodium balance. B: on
sustained increases in salt intake, function curve shifts to the left to give
a higher level of excretion at any given pressure. C: if these adjustments
fail, curve shifts to the right so that a higher equilibrium pressure is
required to match sodium output to input.
A. Role of the Kidney in Hypertension
If the Guyton hypothesis is valid, hypertension results from either a failure to increase sodium output in
response to an increase in intake (i.e., a failure to shift the
renal function curve to the left to produce a higher level
of excretion at any given pressure; Fig. 1, point B) or a
shift in the renal function curve to the right so that a
higher equilibrium pressure is required to match sodium
output to intake (Fig. 1, point C). All forms of hypertension are predicted to be a consequence of abnormal pressure natriuresis responses (107); blood pressure homeostasis is sacrificed to preserve sodium balance.
In several forms of hypertension the underlying
cause of impaired renal natriuretic function is easily identified. Structural changes to the kidney, such as loss of
functional renal mass, or a narrowing of the renal arteries
(stenosis), can impede salt excretion and increase the risk
of hypertension, especially when combined with increased salt intake, as demonstrated by the one-kidney,
deoxycorticosterone acetate rat model and by Goldblatt’s
two-kidney, one-clip model (18). In some cases, a clear
underlying genetic defect can be identified. All of the
Mendelian hypertensive disorders arise from mutations in
genes encoding proteins directly or indirectly involved
with renal sodium handling [see review by Lifton et al.
(192) and below].
B. Impaired Renal Sodium Excretion as a Risk
for Hypertension
The kidney is usually histologically normal in the
early stages of essential hypertension. Nevertheless, a
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Primary or essential hypertension is defined as high
blood pressure where no obvious secondary causes, such
as renal disease, adrenal tumor, drug therapy, or diabetes,
have been identified. Given the large number of environmental, behavioral, and genetic factors that can potentially influence blood pressure, essential hypertension
covers a wide range of underlying causes, and although it
would be extremely useful to subdivide essential hypertension for the purposes of treatment, the parameters for
doing so are not clear-cut (41). Given the polygenic nature
of blood pressure homeostasis, any change due to mutation is likely to be redressed by feedback, complementary
action, or change in some other control mechanism, in an
effort to return blood pressure to normal. The genetic
complement of an individual may determine his/her ability to respond to such change, or to impinging environmental factors. It is only when the balance is sufficiently
disturbed, when checks and balances fail to counteract
the perturbation, that essential hypertension results. Thus
the presenting picture can often give little clue to the true
underlying cause or causes of the hypertension.
TRANSGENICS AND HYPERTENSION
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from the normotensive Brown-Norway rat have markedly
lower blood pressures than noncongenic SHR rats (55).
Elegant cross-transplantation studies between progenitor
SHR rats and the congenic strain revealed that the BrownNorway fragment of chromosome 1 lowered blood pressure. It is important to note that the hypotensive effect
was observed whether the fragments were present renally
or extrarenally, indicating again that other factors exert
powerful influences on MABP (57).
C. Vascular-Dependent Hypertension
It can be difficult to envisage a central role for the
kidney in the onset of hypertension, since gross renal
abnormalities are mostly absent in the early stages of the
disease. Moreover, volume expansion and increased cardiac output would be expected if blunted natriuretic capability plays a primary role in essential hypertension, but
neither of these are cardinal features. Guyton’s hypothesis argues that the period during which blood pressure is
volume-dependent may only be transitory (104), since
elevation of MABP would increase renal salt excretion to
restore sodium balance. Failure to return blood pressure
to normal is attributed to autoregulatory vasoconstriction
in the peripheral vascular beds, triggered locally in response to prolonged exposure to high perfusion pressure.
Despite the fact that chronic hypertension, under this
model, is maintained by the vasculature, impaired renal
sodium excretion remains the initiating event. Data in
support of this hypothesis, such as studies showing that
prevention of volume expansion following salt loading in
DS rats prevents the development of hypertension (95),
are reviewed elsewhere (105).
Nevertheless, other studies in salt-sensitive hypertensive models do not find volume expansion to be a key
hypertensive event (168, 273). It is known, for example,
that an increase in sympathetic nervous system (SNS)
activity is often observed in the early stages of hypertension (146). It has been proposed (143) that this increase in
sympathetic drive is the initiating hypertensive event.
These data suggest that repeated intermittent bouts of
sympathetic hyperactivity cause renal vasoconstriction
and promote subclinical changes to the renal structure,
particularly the afferent arteriole, which in turn leads to
altered salt handling (141). Impaired renal sodium excretion persists as a key feature for hypertension but is no
longer the initiating event. Instead, the hypertension becomes Guytonian only after the kidney is subjected to
repeated ischemic episodes following vasoconstriction
and reduced renal plasma flow (142). Moreover, this may
be a vicious circle in that small increases in plasma sodium concentration can exert a central pressor effect via
activation of both the RAS and SNS (69). For the purposes
of the present review, it is unnecessary to reconcile these
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wealth of data, obtained from both humans and experimental models, suggest that an inadequacy in terms of sodium
excretion is a risk factor for essential hypertension.
A variety of approaches have found that an inability to
excrete sodium leads to increased blood pressure in humans
and experimental animals (382). On intravenous infusion of
saline, renal sodium excretion is markedly blunted in patients with essential hypertension (209). In a subset of essential hypertensive patients, the “salt retention” is associated with impaired pressure natriuresis response (208). Evidence for the causal link between high salt intake and high
blood pressure has been reviewed elsewhere (225).
Cross-transplantation of kidneys between normotensives and hypertensives have provided strong evidence that
the kidney plays a key role in primary hypertension (98).
Studies in humans show a normalization of blood pressure
in six hypertensive patients who, following bilateral nephrectomy, received kidney transplants from normotensive
cadaver donors (63). These patients, in whom high blood
pressure was resistant to a four-drug antihypertensive treatment, showed a prolonged (⬃4 yr) lowering of MABP without the need for therapeutic intervention. Conversely, it is
noted that the incidence of hypertension in transplant recipients correlated strongly with the familial incidence of hypertension in the donor’s family (99).
Several independent groups performed rodent crosstransplantation studies in the 1970s. Dahl’s original findings (65), confirmed later in a number of studies (119, 227,
279, 313), found that on a 0.3% salt diet, blood pressure
was “determined by the genotype of the donor kidney
rather than by the genotype of the recipient.” Interestingly, the insertion of a control kidney into a DS rat did
not prevent blood pressure increases, evoked by a highsalt diet (8%), indicating that extrarenal factors also exert
a significant influence on MABP. One possible criticism of
these experiments is that they demonstrate the effect of
transplanting a kidney already damaged by exposure to
sustained hypertension. This issue was addressed in
young, Milan hypertensive (MH) rats, studied before the
onset of hypertension. Insertion of a normotensive control kidney into a bilaterally nephrectomized MH rat prevented development of hypertension, whereas insertion
of an MH kidney into a control rat induced chronically
elevated MABP (83). Likewise, cross-transplantation of
kidneys from spontaneously hypertensive (SHR) rats,
given life-long antihypertensive therapy by angiotensin
converting enzyme (ACE) inhibition, and never therefore
exposed to high perfusion pressure, conferred hypertension on the genetically normotensive recipient (278).
The studies described above suggest that 1) blood
pressure can be set by the kidney and 2) the renal defect
is genetically determined. Congenic approaches have
been used to localize the genomic region responsible for
setting of blood pressure by the kidney. For example,
congenic SHR rats carrying a segment on chromosome 1
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observations, the germane point being that the kidney
remains central to the misregulation of MABP.
III. ADDITIONAL HYPERTENSION
RISK FACTORS
A. Environmental
B. Ontogenic
There are several distinct developmental windows
during which certain stimuli affect long-term development of the cardiovascular phenotype. For example,
short-term treatment of genetically hypertensive rats with
antihypertensive drugs, at 5–9 wk of age, has a long-term
beneficial effect (118). If hypertension is deferred, then
blood pressure elevation, cardiovascular hypertrophy,
and end-organ damage are considerably attenuated, compared with rats developing hypertension during the critical period in development (118, 354). Immature rats are
highly susceptible to increased salt intake, whilst dietary
calcium has antihypertensive effects. Dietary protein intake also affects blood pressure in juvenile rats (395). An
in depth review of dietary salt and development of salt
sensitivity has been published elsewhere (225).
It is important to study animals in the transitory
phase, when blood pressure is developing, in addition to
analyzing the established hypertensive phase. Genetic alterations that occur in the latter phase are likely to reflect
mechanisms of target organ damage such as left ventricular hypertrophy, rather than the hypertension per se. In
this regard, the inducible hypertensive rat model (153),
which places time course and extent of hypertensive damage in the hands of the investigator, should prove invaluable.
The recent description of a mitochondrial tRNA mutation being linked to hypomagnesemia, hypertension,
and hypercholesterolemia, each of which showed variable
penetrance, poses the interesting possibility that loss of
mitochondrial function with age might also contribute to
age-related increase in blood pressure (379).
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There has been much debate regarding birth weight
as a predictor of future hypertension, stemming from
observations that lower birth weight was associated with
higher death rate from coronary heart disease and stroke
(19). There seems to be a small but consistent inverse
relationship between birth weight and later blood pressure: a 1-kg increase in birth weight correlates to a 1- to
2-mmHg decrease in SBP (78).
In rats, severe sodium restriction during the last week
of gestation causes intrauterine growth retardation and subsequently leads to high blood pressure and renal dysfunction
in adulthood (21). Treatment of rats with dexamethasone (a
poorly metabolized corticosteroid), during the last week of
pregnancy, also causes a reduction in birth weight, glucose
intolerance, and increased adult blood pressure. Additionally, carbenoxolone (an inhibitor of 11␤-hydroxysteroid dehydrogenase type 2, Hsd11b2) treatment in the last trimester
leads to postnatal hyperglycemia, increased blood pressure
in adult progeny, and tissue-specific increases in glucocorticoid receptor density leading to increased cortiscosteroid
sensitivity (29, 308). Glucocorticoids affect glomerular number and kidney maturation (178) but may also affect blood
pressure by altering renal and vasculature catecholamine
receptor levels, by inducing growth factors such as insulinlike growth factor (IGF), by indirect effects on carbohydrate
and fat metabolism, or through increased vasoconstriction
via regulation of catecholamines, nitric oxide, and angiotensinogen synthesis (30).
The level of protein intake in pregnant rats is inversely
proportional to blood pressure in adult offspring (207), although blood pressure can be normalized by treatment with
ACE inhibitors at 8 wk of age. Protein restriction causes
placental enlargement and is characterized by decreased
Hsd11b2 activity, and thus reduced placental protection of
the fetus against maternal corticosteroids (29). Exposure of
the fetus to high glucocorticoid levels may adversely affect
the fetal hypothalamo-pituitary-adrenal (HPA) feedback
system that regulates adrenal output. This is likely to have
an immediate effect on fetal growth but may also reset the
fetal HPA axis, with effects persisting into adulthood.
Current evidence suggests that key targets for programming include the HPA axis, the glucocorticoid receptor
gene, and Hsd11b2 gene expression (30).
In 1988, Brenner et al. (38) suggested that nephron
number was inversely related to MABP. This was based
on the observation that inbred hypertensive rats (SHR for
example) tended to have smaller kidneys and fewer
nephrons than normotensive controls. Similarly, a reduction in nephron number has been found in adults with
essential hypertension; whether this is cause or effect
remains unknown. Low nephron number does not initially
manifest as a reduction in whole kidney glomerular filtration rate, since hyperfiltration of individual glomeruli
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Apart from age and gender, environmental factors
contributing to persistent or pathological changes in
blood pressure include poor diet, lack of exercise, increased body weight, stress, and smoking or alcohol intake. Dietary factors thought to have adverse effects on
blood pressure include high sodium, especially in combination with low potassium (383). Also, higher caloric
intake, reflected in weight gain and increased adipose
tissue, correlates strongly with increase in blood pressure. It has been estimated that 60 –70% of hypertension is
attributable to adiposity, with 5 mmHg increase in systolic
blood pressure (SBP) for every 5 kg weight gain (152).
C. Prenatal Programming
TRANSGENICS AND HYPERTENSION
D. Genetic
As already mentioned, blood pressure is influenced
by a wide variety of physiological systems, that have
pleiotropic effects, and interact in complex ways. These
include the baroreceptors, which detect acute changes in
blood pressure, but are not yet defined at the molecular
level; the renin-angiotensin-aldosterone and kinin-kallikrein systems, which influence sodium retention in the
kidney and vascular tone; natriuretic peptides produced
in response to local increased pressure in the heart and
brain; the adrenergic receptor system, which affects cardiac contraction and vascular tone; dopamine receptors,
which affect natriuresis; vasodilators such as nitric oxide;
and vasoconstrictors such as endothelin. The distinction
between primary alteration and secondary adaptive response contributing to long-term high blood pressure may
be extremely difficult to discern.
Candidate genes are identified in a number of ways.
In some cases, a simple Mendelian form of hypertension
(or hypotension) can be identified by pedigree analysis.
Detailed linkage analysis may then reveal the chromosome, the subchromosomal region, or even the gene most
likely to be involved. Once variants that cosegregate with
the hypertensive phenotype have been identified, then
detailed sequence analysis may identify the causative genetic mutation. Examples of this include Liddle’s syndrome, caused by a mutation in the ␤- or ␥-subunits of
epithelial Na⫹ channel (ENaC) (110, 315).
When hypertension is the result of a complex genetic
trait, the power of linkage analysis is more limited. Hypertension may be the result of small increments in blood
pressure due to a number of contributing gene variants.
Each of these may vary not only in phenotype but may
also be affected by polymorphic allele frequencies, low
penetrance, and the epistatic effects of other genes. As a
consequence, the positions of the quantitative trait loci
may fall below detectable LOD (logarhythmic odds)
scores, or at best identify very large chromosomal regions.
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Genome-wide linkage analyses, which systematically
evaluate the human genome for segments containing
genes that influence blood pressure, have to be carefully
designed (68) and may identify different regions in different populations (172, 385) or even fail to identify any
contributing regions (155). These studies suggest that
different sets of genes contribute to hypertension in different ethnic groups and that precise analysis is difficult
in humans because of their heterogeneous genetic background. Such analyses have been improved by increasing
the density of markers, restriction fragment length polymorphisms (RFLPs), single nucleotide polymorphisms
(SNPs), and microsatellites, throughout the genome. Recently developed microsatellite databases for the human
(58) and the mouse (352) greatly aid whole genome scans.
With the complete analyses of human (221), mouse
(248), rat (90), and now chimpanzee (53a) genomes being
published, conserved synteny for blood pressure quantitative trait loci (QTLs) will hopefully refine the chromosomal location of blood pressure regulating loci (396).
Moreover, comparisons of whole genomes (60) are beginning to reveal highly conserved functional sequences outside the coding sequence of the genes themselves (243).
These are short- and long-range cis-regulatory sequences
controlling the spatial and temporal expression patterns
of the gene or the entire locus (242). Variation in these
regions can have as dramatic an effect on gene expression
as a mutation within the coding region.
An additional source of candidate genes arises from the
study of defects underlying the numerous animal models
selected for hypertensive phenotype (276). These include
the SHR, the Dahl salt-sensitive rat, and the Milan rat. A
wealth of knowledge has been, and continues to be, accumulated for these models, which often prove to be highly
complicated. In fact, the selective breeding strategies that
generated the models are likely to have “fixed” many allele
variants and modifier genes affecting blood pressure homeostasis so that the underlying etiology may not be at all
clear. [It should be noted that breeding of strains at different
establishments can cause further “fixation” of variants, leading to the development of sublines (6, 92).]
Nevertheless, QTL analyses in animals can be highly
informative, because of the large numbers of progeny that
can be screened. This phenotype-driven approach (332)
capitalizes on natural variation among inbred strains (214,
289). By using crosses between two inbred mouse strains
(screening F2 progeny), QTLs associated with blood pressure, heart rate, and heart weight were identified (331).
The recombinant inbred strain platform, generated between the SHR and the Brown-Norway rat (270, 272), has
been useful for identifying QTLs for numerous cardiovascular phenotypes including arterial pressure. The development
of a new framework marker-based linkage map, which
clearly defines the strain distribution patterns (137), will
greatly enhance the utility of these recombinant inbred (RI)
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compensates. Unfortunately, glomerular hyperfiltration is
associated with accelerated loss of renal function, and a
reduction in nephron number reduces the renal reserve,
i.e., the capacity of the kidney to cope with injury, etc.
Brenner’s hypothesis is that a congenital reduction in
nephron number is prenatally programmed, possibly as a
consequence of low birth weight or protein content of the
maternal diet (200), and this increases the likelihood of
developing hypertension in adulthood, especially in the
setting of elevated salt intake. Protein restriction in the
latter half of pregnancy, when nephrogenesis normally
occurs in the rat, has been found to reduce the number of
nephrons in the developing kidney by almost half. Both
male and female progeny developed salt-sensitive hypertension, although females were less severely affected (381).
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IV. SODIUM BALANCE
Sodium balance is key to the homeostatic control of
blood pressure, and a brief overview of the mechanisms
and enzymes involved in renal salt reabsorption is pertinent in relation to Mendelian and essential forms of hypertension, and to put transgenic models in context.
A. Sodium Transport
Sodium is freely filtered at the glomerulus, with
⬃99% of the filtered load being reabsorbed along the
nephron, by an integrated system of ion channels, ion
exchangers. and ion transporters (Fig. 2A). In the proximal convoluted tubule, ⬃50% of filtered sodium is reabsorbed. Although there are ⬃20 different sodium transporters in the apical membrane, most of these couple to
“substrates” (such as amino acids and carbohydrates),
and collectively they mediate only ⬃10% of the proximal
tubule sodium reabsorption. The sodium-hydrogen exchanger, NHE3, mediates the majority of Na⫹ reabsorption (Fig. 2B).
The loop of Henle as a whole reabsorbs considerable
amounts of sodium (30 – 40% of the filtered load). It is a
heterogeneous nephron segment, consisting of the
straight portion of the proximal tubule (pars recta), the
descending and ascending thin limbs, and the thick as-
FIG. 2. A: percentage sodium reabsorption over the length of the nephron. Principal mechanisms of sodium reabsorption are shown in the
proximal tubule (B), the thick ascending loop of Henle (C), the distal convoluted tubule (D), and the collecting duct (E).
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strains. An equally useful resource is provided by the panel
of consomic rat strains (61), in which an entire chromosome
from one inbred strain is introgressed onto the background
of a second inbred strain. These can be used to assign traits
and QTLs to any given chromosome.
Congenic strains can be rapidly developed using the
marker-assisted speed congenic approach (135) to locate
the QTL more accurately over narrow regions of the
chromosome. Arguably this may disrupt the very genetrait relationships being sought, but consomics with multiple chromosome substitutions, and double congenic
strains, can be used to investigate such gene-gene interactions in the future (217). It must be stressed that the
identification of any candidate gene in an animal model
does not automatically imply its involvement in hypertension in humans. This may be due to species specificity, a
topic that will be revisited later in the review, or simply to
a lack of genetic variation in some species.
TRANSGENICS AND HYPERTENSION
B. Tubuloglomerular Feedback
The early distal tubule is the site of the macula densa
(MD), a collection of specialized epithelial cells able both
to “sense” the NaCl concentration of the tubular fluid and
to influence filtration at the glomerulus of origin (Fig. 3).
This mechanism, called tubuloglomerular feedback
(TGF), rapidly stabilizes acute increases in Na⫹ delivery
by vasoconstriction of the afferent arteriole and reduction
in single-nephron glomerular filtration rate (SNGFR): delivery of sodium to the MD is thus held within narrow
boundaries, ensuring that the distal tubule and cortical
collecting duct (CCD) are not overloaded. Equally important is the increase in SNGFR following a drop in distal
Na⫹ delivery, which serves to restore Na⫹ concentration
to levels compatible with the maintenance of K⫹ and H⫹
secretion. TGF responses are rapid, and the sensitivity of
response is dictated by afferent arteriolar tone. Thus TGF
is modulated by agents such as angiotensin II (ANG II),
nitric oxide (NO), and the eicosanoids and can be reset
during chronic perturbations in MD sodium delivery and
altered volume status (299). Moreover, studies in inbred
hypertensive rat strains show that TGF is inappropriately
sensitized during the development of hypertension, i.e.,
GFR, and thus filtered sodium load, is lower for a given
delivery of sodium to the MD than normal, reducing the
ability of the kidney to shed sodium (265).
The basolateral membrane of the MD cells is physically separated from the afferent arteriole by the extraglomerular mesangium. Because no direct cellular contact
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FIG. 3. Structure of the glomerulus, indicating the juxtaposition of
the granular juxtaglomerular cells of the afferent arteriole and the
epithelial cells of the macula densa in the same nephron.
has been demonstrated between them, it is hypothesized
that the first event in juxtaglomerular apparatus (JGA)
communication is paracrine, with controlled, altered
NaCl concentration at the apical membrane of the MD
evoking release of a signaling substance from the basolateral side. Recent studies, using the isolated perfused
JGA, found channel-mediated release of ATP from the
basolateral membrane correlating with luminal NaCl concentration in the physiological range (24, 166). Furthermore, the concentration of ATP in the cortical interstitium responds predictably to inhibition or activation of
TGF in vivo (240). Because the afferent arteriole constricts in response to ATP, an effect mediated by P2X1
receptors, it has been suggested that ATP is the mediator
of TGF [see Unwin et al. (353) for review]. Preliminary
data, however, find that P2X1 receptor knockout mice
display normal TGF responses (297), despite having impaired pressure-induced autoregulation in the afferent
arteriole (133). Gene targeting experiments support the
notion that P1 (adenosine) rather than P2 receptors mediate TGF; in vivo responses are absent in the majority of
tubules from mice lacking A1 receptors (333). It is thus
proposed that hydrolysis of extracellular ATP to adenosine is a prerequisite for TGF, since pharmacological
blockade of hydrolysis (277) or genetic ablation of 5⬘ectonucleotidase (46) attenuates the TGF response.
C. TGF and the Renin-AngiotensinAldosterone System
The intimate connection between TGF and the RAS
is shown by cessation of TGF response in mice lacking
angiotensin AT1A receptors (300). The RAS can certainly
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cending limb (TAL). In the TAL, sodium is reabsorbed
(⬃20% of the filtered load) but water is not, thereby
creating a steep osmotic gradient in the medullary interstitium, which permits vasopressin-dependent water reabsorption in the collecting duct. In the TAL, almost all
sodium transport results directly or indirectly from Na⫹K⫹-2Cl⫺ cotransport (96). Efficient operating of this transporter (NKCC2) requires K⫹ to recycle across the apical
membrane through a K⫹ channel (ROMK) and chloride to
exit basolaterally through a chloride channel (CLCNKB;
Fig. 2C). Potassium recycling creates a potential difference, which drives the reabsorption of cations through
the paracellular pathway. This is especially important for
divalent ions as shown by the hypercalciuria of Bartter’s
disease.
Sodium reabsorption in the early distal tubule (DCT1
and DCT2) is mediated by the thiazide-sensitive NaCl
cotransporter (NCC) (Fig. 2D) and also, to a lesser extent,
by sodium-hydrogen exchange (NHE2). The remaining
reabsorption is achieved in the connecting tubule and
cortical collecting duct via ENaC, and it is this segment in
which the fine-tuning of sodium reabsorption occurs, under the control of aldosterone (Fig. 2E).
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V. EVALUATING CANDIDATE GENES
Before discussing the identities of numerous candidates, we first overview the strategies used to assess their
probable contributions (91). Initially, circumstantial evidence, such as the association of altered protein expression or function of naturally occurring variants with altered phenotype, may provide strong support. Highthroughput gene expression profiling has emerged as a
powerful tool in this respect. For example, microarray
analysis of a rat strain (derived from Wistar-Kyoto and
stroke-prone SHR rats), congenic for a region of chromosome 2, revealed significant reduction in glutathione-Stransferase mu-type 2, a gene involved in oxidative stress
defense, which parallels the observed decrease in systolic
and diastolic blood pressures (216).
Ultimately it is desirable to alter the expression of a
candidate gene, to ascertain or confirm its mode of action,
and the pleitropic effects, including hemodynamic parameters, which might result from altered expression. Detailed analysis of transgenic models may reveal the presence of previously unidentified modifier loci, which attenuate or exacerbate the phenotype, on different genetic
backgrounds.
Genetic modification can be achieved in a number of
ways, including microinjection and homologous recombination. Each strategy is detailed in the following sections.
A. Transgenesis by Microinjection
Transgenesis by microinjection generally leads to
overexpression of the transgene. A transgene construct is
microinjected into the pronucleus of a fertilized oocyte
(see Fig. 4), which is then placed in the oviduct of a
pseudopregnant host and allowed to develop to term.
Resultant pups are screened for potential founders, from
which transgenic lines can be derived. The transgene
integrates at random in the genome; therefore, every
transgenic line is unique. The researcher has no control
over the number of copies inserted, which are present in
addition to the endogenous copies of the gene. The site of
insertion can have a profound effect on expression of the
transgene (114). If it inserts in a silent region of the
chromosome, then expression may be completely suppressed. On the other hand, insertion near a strong enhancer
may result in aberrant patterns of expression. Integration
within a gene may insertionally inactive it, causing a completely unrelated and unexpected phenotype.
Despite these caveats, transgenesis by microinjection
is an attractive option. Effects from sequences flanking
FIG. 4. Generation of transgenic animals by microinjection of fertilized oocytes, transfer to pseudopregnant females, and screening of progeny (e.g., by Southern blot analysis or PCR).
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modulate TGF but represents a distinct mechanism for
regulating sodium excretion depending on the requirements of systemic sodium balance. Thus, if enhanced
sodium delivery to the MD is maintained, then renin secretion is reduced, local ANG II levels fall, and SNGFR
rises to promote sodium excretion. Likewise, reduced salt
levels in the TAL lead to release of renin. Increased renin
levels lead to increased production of ANG II, which acts
on the adrenal glomerulosa cells, via a G protein-coupled
receptor, to increase aldosterone synthase activity, and
thus aldosterone secretion. Aldosterone targets the mineralocorticoid receptors in the distal nephron, and ultimately causes an increase in sodium reabsorption and
potassium secretion. Any mutation that causes sustained
salt retention concomitantly increases water retention
and will thus raise blood pressure. Likewise, any mutation
that causes salt wasting will lead to hypotension.
TRANSGENICS AND HYPERTENSION
Cre-mediated recombination yielding the desired alteration in gene expression.
Reporter strains, which express ␤-galactosidase
(325) or enhanced green fluorescent protein (156, 293)
following Cre recombinase activation, indicate the tissue
specificity and extent of recombination for any given Cre
strain. This should be tested, since Cre expression may be
leaky, ectopic, or mosaic. The latter observation has been
used to advantage, recently, for generating Cre-mediated
germline mosaicism (124, 187). It is also worth noting that
the loxP footprint left behind after Cre recombination
may affect gene expression. (See detailed reviews of conditional transgenic technologies in Refs. 35 and 290.)
B. Gene Targeting
Gene targeting and gene knockout is achieved when
a modified copy of the target gene is introduced into
embryonic stem (ES) cells (Fig. 5). Under appropriate
selective pressure, the transgene replaces the endogenous
gene by homologous recombination. The targeted ES cells
are introduced into blastocysts, where they have the potential to contribute to all tissues of the developing embryo. The resultant chimeric pups are bred to screen for
germline transmission of the transgene. This technique
can be used not only for loss-of-function analysis, but also
for replacement of the targeted gene with a reporter, such
that the developmental and tissue-specific expression patterns of the endogenous gene can be visualized. An obvious potential drawback to loss-of-function targeting is the
possibility of embryonic lethality due to a requirement for
gene expression early in development. To overcome this,
sophisticated strategies for making transgene expression
FIG. 5. Gene targeting by homologous recombination in
embryonic stem (ES) cells, introduction of microinjected
blastocysts into pseudopregnant females, generation of chimeras, and breeding to homozygosity.
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the insertion site can be largely overcome by increasing
the size of the transgene construct. Bacterial artificial
chromosomes (BACs) and P1 artificial chromosomes
(PACs), vectors capable of carrying inserts up to 300 kb,
are used routinely to generate transgenic animals. The
long segments of DNA upstream and downstream of the
gene of interest act as a buffer against effects from flanking sequences. As a bonus, the transgene construct is
more likely to include both short-range and long-range
control elements, making correct tissue-specific and developmentally specific transgene expression more likely.
The BAC or PAC may also include other genes, and the
researcher must be aware of any interactions between these
genes, or their control elements, and the gene of interest, or
again unexpected phenotypes may occur (233, 241).
With the development of homologous recombination
systems in Escherichia coli (184, 236), BACs and PACs
can be easily engineered to carry reporter genes, or to
place the transgene under the control of inducible or
conditional promoters. There are sophisticated systems
for conditionally turning genes on or off by dietary
changes (153), or antibiotic induction or suppression
[e.g., using tetracycline/doxycycline (394)]. Strategies using the Cre-lox recombination system (237) or FRT-flp
technology (281) have proven particularly useful. A detailed discussion is beyond the scope of this review, but it
is worth pointing out that many of these strategies require
the generation of two independent transgenic lines. For
example, one line might carry the transgene of interest,
flanked by loxP sites (floxed) to allow conditional knockout, or have an upstream floxed stop cassette to allow
conditional knock-in. The second line would carry tissuespecifically or developmentally expressed Cre recombinase. Crossing the two lines would result in conditional
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conditional are available. With the advent of BAC homologous technology, much larger targeting constructs can
be engineered, and multiple alterations can be achieved in
one round of ES cell recombination (344). High-throughput engineering technology is now established, which can
replace precisely any given gene of interest with a reporter, or generate point mutations or deletions (355).
Coupled with high-resolution expression analysis, this
will be a powerful tool in functional genomics.
C. RNA Interference
VI. MENDELIAN HYPERTENSION
As already noted, where hypertension can be shown
to result from mutations in a single gene, exhibiting classic Mendelian inheritance, it has been found to affect,
without exception, net renal salt reabsorption (192). Recently, mutation in a mitochondrial tRNA, exhibiting maternal (i.e., non-Mendelian) inheritance, was shown to be
the cause of hypomagnesemia, hypertension, and hypercholesterolemia in a large Caucasian kindred (379). The
Mendelian forms of hypertension fall broadly into three
classes: those that affect levels of circulating mineralocorticoids, those that affect the mineralocorticoid receptor, and those affecting renal ion transport (see Fig. 6).
(For a detailed review, see Ref. 192).
A. Mineralocorticoid Hormone
1. Aldosterone synthase
Aldosterone synthase deficiency, arising through either point mutation or microdeletion (261), results in
FIG. 6. The action of aldosterone on the mineralocorticoid receptor leading to salt reabsorption by
ENaC. Mendelian forms of hypertension and hypotension arising from mutations in components of the pathway are noted.
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RNA interference, using small interfering RNAs
(siRNAs), is a powerful new tool for analyzing gene
knockdown phenotypes. RNA interference is an evolutionarily conserved mechanism mediated by doublestranded microRNA (miRNA), which targets mRNA for
degradation by cellular enzymes, effectively limiting
translation by binding to sites within introns, or in the
3⬘-untranslated region (139). The dsRNA is processed into
small duplex RNA molecules (20 –25 nucleotides) by an
RNase III enzyme called dicer. The siRNAs interact with
an RNA-induced silencing complex, leading to sequencespecific binding and cleavage of the target mRNA. Introduction of siRNA molecules directly into somatic mammalian cells circumvents the nonspecific response against
larger dsRNA molecules (53).
At present, knockout technology is not available for
the rat, since rat ES cells have proven technically difficult
to produce. Chemically synthesized siRNAs and short
hairpin RNAs (shRNAs) have recently been shown to
transiently or stably knock-down gene expression in
transgenic mice and, significantly, in rats (113, 189, 218,
257). This technology, together with others discussed in
future perspectives, promises to widen the application of
transgenic technology to the rat and other species.
TRANSGENICS AND HYPERTENSION
2. 11␤-Hydroxylase deficiency
The complementary hybrid gene resulting from unequal crossover between 11␤-hydroxylase and aldosterone synthase places the chimeric gene under the aldosterone synthase promoter (108, 267). The gene is induced
by ANG II and K⫹, and its expression is restricted to the
zona glomerulosa, leading to 11␤-hydroxylase deficiency,
hypertension, and congenital adrenal hyperplasia (CAH).
The most common cause of CAH (accounting for 90%
of cases) is 21-hydroxylase deficiency, while up to 8% of
classic CAH is caused by 11␤-hydroxylase deficiency (375).
Decreased or absent cortisol secretion stimulates ACTH
secretion, which results in accumulation of steroid precursors and increased androgen levels. Patients suffer from
masculinization and short adult stature due to precocious
pseudopuberty, and increased levels of deoxycorticosteroid
may cause hypertension because of its mineralocorticoid
activity. The nonclassic form of 11␤-hydroxylase deficiency
has milder symptoms and is characterized by missense mutations, which have been shown to affect enzyme activity
in vitro (138). Severity of symptoms appears to be determined by the nature of the point mutation or deletion in
the gene (171). No transgenic models of 11␤-hydroxylase
(Cyp11b1) deficiency have been reported to date.
3. Syndrome of apparent mineralocorticoid excess
The syndrome of apparent mineralocorticoid excess
(SAME) is autosomal recessive and occurs when the enPhysiol Rev • VOL
zyme HSD11B2 is defective. This enzyme normally converts active cortisol (or corticosterone in rodents), which
can act at the mineralocorticoid receptor (MR) to inactive
cortisone (or 11-dehydrocorticosterone), effectively protecting the receptor from the high circulating levels of
cortisol. In SAME, physiological levels of glucocorticoids
illicitly activate the MR in the distal tubule. This leads to
sodium retention, early-onset hypertension, hypokalemia,
and alkalosis, but additionally, suppressed plasma renin
and absence of circulating aldosterone are observed due
to feedback inhibition. Interestingly, glycyrrhetinic acid,
the active ingredient of licorice, inhibits HSD11B2 and
induces hypertension, presenting as pseudohyperaldosteronism (358).
A mouse transgenic model, in which Hsd11b2 was
knocked out (169), developed early-onset hypertension
and demonstrated major features of SAME, including
polyuria and hypokalemia. Homozygous mutants appear
normal at birth, but 50% show motor weakness and reduced suckling, and die within 48 h, presumably related to
the severity of hypokalemia. Surviving null animals exhibit enlarged kidneys, associated with distal tubule enlargement due to hyperplasia and hypertrophy of epithelia. Administration of dexamethasone (the synthetic glucocorticoid, which suppresses the HPA axis and hence
corticosterone production), which is not a ligand for MR,
increases the urinary Na⫹/K⫹ ratios to wild-type levels
(see Fig. 7), while electrolyte abnormality is recreated
following corticosterone administration (123).
B. Mineralocorticoid Receptor Mutations
1. Pseudohypoaldosteronism type I
Pseudohypoaldosteronism type I (PHA-1) is an autosomal dominant condition caused by loss-of-function mutations in the mineralocorticoid receptor (89). Despite
elevated levels of aldosterone, affected patients have severe neonatal salt wasting and hypotension, with hyperkalemia and metabolic acidosis. The MR deficiency is
potentially lethal, suggesting that two copies of functional
MR are required by the neonate. All cases improve with
age, and by adulthood, a normal-salt diet is asymptomatic.
Mineralocorticoid receptor (Nr3c2)-deficient mice
die around day 9 or 10 after birth. By day 8, the animals
show symptoms of pseudohypoaldosteronism, with high
levels of plasma renin, ANG II, and aldosterone, high renal
salt wasting, hyponatremia, and hyperkalemia (27, 127).
They also exhibit histological changes in the kidney, with
enlargement of the macula densa segment of the distal
tubule and recruitment of renin-producing cells along the
afferent arteriole. Daily subcutaneous injections of isotonic NaCl solution until weaning, followed by continued
oral NaCl, rescue the pups (34). Under these conditions,
plasma Na⫹ concentration is normal, but the animals
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severe impairment of salt reabsorption, leading to reduced plasma volume and severe hypotension, and impaired secretion of K⫹ and H⫹ leading to hyperkalemia
and acidosis. Mice completely lacking aldosterone synthase (Cyp11b2) have been reported to have a broadly
similar phenotype (185): hypotension, abnormal electrolyte homeostasis, and increased urine production, together with high levels of circulating renin and ANG II.
They also showed increased cyclooxygenase-2 (COX-2)
expression in the macula densa, which was somewhat
enlarged (206). Interestingly, all the abnormalities, except
for low blood pressure, were substantially corrected on
administration of a high-salt diet.
Glucocorticoid remedial aldosteronism (GRA; Ref. 261)
occurs when unequal crossing over between aldosterone
synthase and the closely related gene 11␤-hydroxylase puts
aldosterone synthesis under the control of adrenocorticotropic hormone (ACTH), which normally controls adrenal
11␤-hydroxylase expression and cortisol secretion. Constitutive aldosterone secretion causes sodium retention, increased plasma volume and blood pressure, and increased
secretion of K⫹ and H⫹, leading to hypokalemia and alkalosis. As the name suggests, exogenous glucocorticoids completely suppress the aldosterone secretion, through negative
feedback of ACTH production.
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Overexpression of the human mineralocorticoid receptor in mice (directed by its P1 promoter, which is
transcriptionally active in all MR-expressing tissues and
importantly directs appropriate transgene expression in
the distal nephron) leads to alterations in cardiac and
renal functions. These mice have a decreased urinary
sodium/potassium concentration ratio, consistent with an
increased aldosterone action in the connecting tubule and
collecting duct, and this is exacerbated on sodium depletion (186).
C. Mutations Altering Renal Transport Proteins
remain hyperkalemic, their fractional renal excretion of
Na⫹ (FENa) is still enhanced and plasma renin and aldosterone levels remain high. Interestingly, the mRNA abundance of ␣-ENaC is reduced by 30% in the kidney (though
that of the ␤- and ␥-ENaC subunits is unaltered) and
ENaC activity is almost absent. Recently, it has been
shown that glucocorticoid treatment restores plasma K⫹
and almost normalizes FENa (304). This is achieved by
increasing the mRNA abundance of ␣-ENaC in the kidney.
Interestingly, cardiac-specific, conditional expression of an antisense mRNA of murine MR caused cardiac
fibrosis and heart failure in the absence of chronic hypertension or chronic aldosteronism (22). Antisense mRNA
could be up- or downregulated by Tet or Dox, respectively, the latter leading to rapid improvement. This model
demonstrates the potential to interrogate gene function in
specific cell types, rather than by constitutive alteration,
which has both systemic and local effects.
As further evidence for the involvement of MR in
hypertension, a missense mutation in the mineralocorticoid receptor ligand-binding domain has been shown to
cause an autosomal dominant form of hypertension accelerated by pregnancy. The missense mutation renders
the receptor activatable by steroids that would not normally bind to MR, including progesterone. Because progesterone levels increase 100-fold during pregnancy, a
rapid acceleration of hypertension associated with complete suppression of the RAS is observed (88).
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1. Proximal convoluted tubule
The Na⫹/H⫹ exchanger, NHE3, is the major pathway
for sodium reabsorption in the proximal tubule (see Fig.
2B), and as such, knockout of the exchanger would be
expected to markedly impair tubule function and result in
renal salt loss. However, despite a significant (50 – 60%)
reduction in proximal tubule fluid reabsorption, NHE3
(Slc9a3) knockouts have only mild volume depletion and
hypotension (301, 374). A major compensatory mechanism is the reduction in SNGFR that reduces filtered
sodium load to match impaired proximal reabsorption
capability or capacity, to the extent that delivery to the
end of the tubule segment is comparable to that in controls (197). SNGFR is reduced through the action of TGF.
Because sodium delivery to the macula densa is not increased in Slc9a3 ⫺/⫺ mice, chronic volume depletion
must cause resetting of the TGF response.
A “targeted proteomics” approach (semiquantitative
immunoblotting), profiling sodium transporter expression
along the entire renal tubule (40) demonstrated upregulation of both the proximal tubule Na⫹-phosphate cotransporter, and the collecting duct ␥-ENaC subunit. Upregulation of NHE2 in the early distal tubule has also been
demonstrated (16). Together with the reduced GFR,
changes in transporter expression (which may relate to
the increased aldosterone and renin levels, Ref. 301) compensate for the loss of NHE3 so efficiently that absolute
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⫹
⫹
FIG. 7. The urinary Na /K concentration ratio in 11␤-hydroxysteroid dehydrogenase type 2 (Hsd11b2) null mice (circle) or wild-type
littermates (square). On vehicle administration, the Na⫹/K⫹ ratio is
significantly lower in Hsd11b2⫺/⫺ mice than controls, consistent with
enhanced mineralocorticoid activity in the distal nephron. Dexamethasone treatment restores the Na⫹/K⫹ ratio, presumably by suppressing
endogenous glucocorticoid. Administration of exogenous corticosterone in the presence of dexamethasone again reduces the Na⫹/K⫹ ratio,
demonstrating that glucocorticoids act as mineralocorticoids in mice
lacking Hsd11b2 activity.
Animals with null mutations in renal NaCl and water
transporter genes provide a powerful tool for studying the
physiological balance between glomerular filtration rate
and tubular reabsorption (296). In general, all Na⫹ transport deficiencies cause a permanent reduction in extracellular fluid volume, with symptoms such as increased
renin expression and aldosterone synthesis, and a tendency to hypotension. This leads to compensatory activation of Na⫹ conserving mechanisms, such as the TGF. If
Na⫹ balance can be reinstated, then the volume depletion
is self-limiting and a steady state is achieved. When sodium balance cannot be achieved, salt wasting and volume depletion would lead to death.
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TRANSGENICS AND HYPERTENSION
ble knockouts were able to maintain salt balance, despite
having a higher GFR and lower proximal reabsorption
than Aqp1 ⫺/⫺ mice (112). This demonstrates the remarkable redundancy of renal sodium transport and illustrates the compensatory power of distal sodium reabsorption.
2. TAL
Mutations in the Na⫹-K⫹-2Cl⫺ cotransporter, NKCC2,
or any of the genes encoding ion channels required for its
operation (ROMK, CLCNKB) cause Bartter’s syndrome
(see Fig. 8), characterized by severe polyuria, low plasma
potassium, high blood pH, hypercalciuria, proteinuria,
and low blood pressure (116). The importance of Nkcc2
(Slc12a1) is demonstrated by the fact that homozygous
knockout mice die within 2 wk of birth from severe
volume depletion (335). [Animals heterozygous for the
mutation show no phenotype (334).] Indomethacin (a potent nonselective COX inhibitor), administered from
birth, rescues the phenotype, implicating prostaglandins
in the regulation of renal salt excretion. Surviving adults
exhibit all the features of Bartter’s syndrome and develop
severe hydronephrosis.
Null mutations in the ROMK gene cause type II
Bartter’s syndrome in humans, and mouse Kcnj1 knockouts faithfully model this disorder (195, 198). Although
the majority of null mutants die within 3 wk of age,
survivors have reduced NaCl absorption in the TAL and a
marked renal sodium loss despite the reduction in GFR.
FIG. 8. Syndromes characterized by reduced sodium reabsorption across the latter sections of the
nephron.
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urinary sodium excretion is significantly lower in knockouts than controls (16, 40). The volume depletion and
hypotension may relate to salt/fluid loss attributed to an
intestinal sodium reabsorption defect, since the knockouts have pronounced diarrhea. In support of this, partial
transgenic rescue through restoration of NHE3 expression in the small intestine improves the volume-pressure
defects (244).
Aquaporin-1 (AQP1) is a water channel highly expressed in the proximal tubule, thin limbs of Henle, and
the vasa recta (363). Aqp1 knockout mice are polydipsic
and have moderate hypotension. Like the Slc9a3 knockout mouse, Aqp1 deficiency results in a marked deficit in
proximal tubule reabsorption which is compensated for
by activation of TGF (298). Loss of Aqp1 in the thin limb
of Henle and in the vasa recta disrupts the countercurrent
multiplication system and thus knockout mice are unable
to concentrate urine in response to water deprivation,
even during administration of vasopressin (363).
From these two examples, it is apparent that impaired proximal tubule function results in modest hypotension, despite the quantitative importance of the proximal tubule in renal sodium reabsorption. This is because
the TGF loop provides a powerful compensatory mechanism, which limits the severity of the genetic defect. One
would predict that an inoperative TGF, coupled with a
proximal tubule disorder, would result in severe salt wasting. To investigate this hypothesis, the Aqp1 ⫺/⫺ mouse
was crossed with the adenosine A1a receptor knockout
mouse, which has a defective TGF. Surprisingly, the dou-
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This lack of compensation, which contrasts with proximal
tubule mutants described above, may result from impaired TGF. K⫹ channels are required for efficient sensing
of luminal sodium by MD cells (356).
Loss-of-function mutations in CLCNKb or its associated protein Barttin produce Bartter’s syndrome types III
and IV, respectively (116). Both proteins (Clcnkb being
the mouse ortholog) are localized to the mouse TAL, but
transgenic models have not yet been reported.
3. Distal convoluted tubule
4. Collecting duct
The autosomal recessive form of human pseudohypoaldosteronism type I is caused by loss-of-function mutations in any of the three ENaC subunits (␣, ␤, and ␥; see
Fig. 8). It is characterized by salt wasting, hyperkalemia,
and high mortality immediately after birth (49, 330). Unlike patients with the autosomal dominant form of
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Sodium reabsorption in the DCT occurs via the apical
thiazide-sensitive NaCl cotransporter (NCC), mutations of
which cause Gitleman’s disease (see Fig. 8). Patients with
Gitelman’s syndrome often present at adolescence with
hypokalemia, metabolic alkalosis, and mild hypotension
(320). In contrast to Bartter’s syndrome, hypocalciuria is
observed as a consequence of an increased driving force
for Ca2⫹ reabsorption in the DCT. Mice lacking NCC
(Slc12a3) have no overt salt wasting phenotype unless
sodium restricted (302). A targeted proteomics approach
noted an increase in ␥-ENaC in Slc12a3 knockout mice
(40), relating perhaps to stimulation of the RAS.
Patients with Gordon’s syndrome (pseudohypoaldosteronism type II, a rare autosomal dominant condition)
exhibit low-renin low-aldosterone hypertension, hyperkalemia, and metabolic acidosis. The syndrome can be corrected with thiazide diuretics, suggesting increased NCC
activity as the underlying cause. There is, however, no
significant linkage between Gordon’s syndrome and the
NCC gene (SLC12A3) locus (85). The clinical features, in
a subset of these patients, arise from independent mutations in two members of a serine-threonine kinase family,
WNK4 (378), and WNK1 (239) which regulate sodium and
potassium transport proteins in the distal nephron. The
hypertension stems from both impaired retrieval of NCC
from the apical membrane of the DCT cell (380) and
increase in paracellular chloride flux (147). The hyperkalemia arises from a gain-of-function mutation in WNK4
(independent of its kinase activity), which increases the
inhibition of K⫹ secretion via endocytotic retrieval of
ROMK (148). Thus WNK4 has a dual role in controlling
renal sodium and potassium excretion (33). The association between an SNP near the WNK1 promoter and severity
of hypertension suggests that increased WNK1 expression
might also contribute to increased blood pressure (239).
pseudohypoaldosteronism type 1, patients fail to improve
with age and require massive salt supplementation. Mice
with knockout mutations in the Scnn1b or Scnn1g genes
encoding the ␤- or ␥-subunits of the sodium channel die
shortly after birth from dehydration and hyperkalemia
(20, 219). Mice with targeted deletion of the ␣-subunit
(Scnn1a) die from failure to clear their lungs (128). Mice
expressing an ␣-ENaC transgene on an Scnn1a knockout
background have 50% perinatal mortality, and salt wasting, but can compensate for the deficiency as adults (129).
Animals surviving to adulthood develop compensated
pseudohypoaldosteronism, though aldosterone levels are
sixfold higher than normal (371). These observations suggest that Na⫹ malabsorption in the terminal nephron
causes severe salt wasting and that compensatory mechanisms for severe volume depletion in the newborn are
relatively inefficient under these conditions. Interestingly,
when ␣-ENaC was specifically inactivated in the collecting
duct only, knockout animals were completely viable. This
points to the connecting tubule as being critical for achieving sodium and potassium balance (288).
When the Scnn1b gene is “knocked down” and mRNA
expression is reduced to 1% of wild-type levels in mouse
kidney and lung (268), homozygous mutants develop normally on a normal-salt diet. Adults exhibit significantly reduced ENaC activity in the colon and increased levels of
plasma aldosterone, but they have normal plasma Na⫹ and
K⫹ concentrations, normal blood pressure, and no weight
loss. On a low-salt diet, however, the mice develop acute
pseudohypoaldosteronism type 1, indicating that ␤-ENaC is
important for Na⫹ conservation during salt deprivation.
Liddle’s syndrome is characterized by early-onset hypertension, hypokalemic alkalosis, suppressed plasma renin activity, and low plasma aldosterone levels. The autosomal dominant syndrome is caused by mutations at the
conserved PY motif in either the ␤- or the ␥-subunit of
ENaC, which delete or modify their cytoplasmic COOH
termini, resulting in increased ENaC activity (294), and
increased water and salt reabsorption in the renal collecting tubules. The number of channels in the membrane is
effectively increased due to their reduced clearance from
the cell surface. Normally, a ubiquitin-protein ligase,
Nedd4, binds to the PY motif of ENaC subunits leading to
ubiquitination and degradation. In cells derived from the
mouse collecting duct, it has been shown that Nedd4 –2 is
the isoform responsible for binding to the ENaC complex
and negatively regulating it (150, 151; see Fig. 6). No
knockout models of Nedd4l have as yet been published,
but in vitro analysis has shown that siRNA against
Nedd4 –2 specifically increases amiloride-sensitive Na⫹
current (324), whilst the mutation associated with Liddle’s syndrome (␤R566X) abolishes the effect of the siRNA.
A mouse model for Liddle’s syndrome has been generated by Cre/loxP-mediated recombination (269). Animals heterozygous for the ␤-ENaC-mutated allele contain-
TRANSGENICS AND HYPERTENSION
VII. ESSENTIAL OR MULTIGENIC
HYPERTENSION
genes showing simple Mendelian inheritance, the pattern
of inheritance is not clear-cut, despite a 30% genetic contribution, and suggests that essential hypertension is determined by the actions of multiple genes and results from
the unfortunate, random combination of small genetic
variations that alone might not be considered harmful.
Subdivision of the hypertensive population into more homogeneous genetic subgroups, or intermediate phenotypes, should restrict the number of genes involved in
each subgroup. For example, “nonmodulating” hypertension is characterized by inappropriate adrenal and renal
vascular responses to ANG II infusion (377), with reduced
renal blood flow during high salt intake and reduced
aldosterone response during low salt intake. Such subdivision would also allow more appropriate or relevant
treatment to be administered.
We have already considered the many strategies for
confirming candidate genes in animal models of monogenic hypertension. We will now review some of the
transgenic experiments, which have identified potential
contenders for involvement in dysregulation of blood
pressure. These are considered within their specific control systems and pathways, but it must be stressed that
the latter do not occur in isolation. Interactions between
the different pathways are alluded to where pertinent. We
have limited our discussions to transgenes that show
clear renal versus systemic actions.
A. Renin-Angiotensin System
The aspartyl protease renin specifically cleaves angiotensinogen to produce the decapeptide ANG I. This is
cleaved by ACE to yield the active octapeptide ANG II
(see Fig. 9A). ANG II acts through angiotensin receptors
AT1 and AT2 to effect aldosterone production in the zona
glomerulosa of the adrenal gland, to affect vascular tone,
and to feedback on the juxtaglomerular cells of the kidney, to control renin production. The involvement of components of the RAS in hypertension is undisputed, despite
the lack of strong QTL association with primary hypertension, or families with severe mutations. In high-renin
hypertension and nonmodulating hypertension, the RAS
is inappropriately active, and the effectiveness of ACE
inhibitors and AT1 blockers as antihypertensive agents
points to its key role in determining blood pressure. Recently, mutations in RAS genes have been associated with
autosomal recessive renal tubular dysgenesis, highlighting their crucial role in kidney development (97), and a
strong association between renin intronic dimorphism
and essential hypertension has been identified in United
Arab Emirate populations (4).
1. Renin transgenics
Essential hypertension is characterized by high blood
pressure without any obvious cause. Instead of single
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In the human and the rat, there is only one renin
gene. Some strains of mice, such as C57BL/6, also contain
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ing the floxed neo gene were crossed with hemizygous
mice ubiquitously expressing the EIIa-Cre transgene.
Mice showing complete excision of the neo gene were
then used to generate new mouse lines. Under normal-salt
diet, mice heterozygous (L/⫹) and homozygous (L/L) for
the Liddle mutation (L) develop normally during the first
3 mo of life. Blood pressure is normal, despite increased
sodium reabsorption in the distal colon and low plasma
aldosterone, suggesting chronic hypervolemia. Under
high salt intake, the Liddle mice develop high blood pressure, metabolic alkalosis, and hypokalemia accompanied by
cardiac and renal hypertrophy. This animal model reproduces to a large extent the human form of salt-sensitive
hypertension and establishes a causal relationship between
dietary salt, ENaC expression, and hypertension.
The earliest effect of aldosterone is to increase ENaC
activity without increasing its mRNA or protein levels, suggesting the presence of an ENaC regulator. To identify aldosterone-stimulated gene products that modulate ENaC activity, a subtracted cDNA library was generated from a renal
distal nephron-derived cell line (50). With the use of a coexpression assay, a serum and glucocorticoid-regulated kinase,
sgk, was found to stimulate ENaC activity sevenfold in Xenopus laevis oocytes. Induction of sgk mRNA by aldosterone was detected in kidney cortex and medulla as early as
30 min after hormonal application, and independent of de
novo protein synthesis, suggesting that the response is mediated by occupancy of mineralocorticoid receptor (314).
Sequence comparison has revealed a homologous serinethreonine kinase in rats and frogs, suggesting an ancient
kinase adapted to control epithelial Na⫹ transport (264).
The sgk knockout mouse was found to have impaired
ability to retain renal Na⫹ (384) when placed under dietary NaCl restriction, despite increases in plasma aldosterone. Unlike most serine-threonine kinases, SGK1 is
under dual control: protein levels are controlled by aldosterone, through effects on gene transcription, while its
activity is dependent on phosphatidylinositol 3-kinase
(PI3K) activity. Thus insulin and other activators of PI3K
are key regulators of SGK1. SGK1 exerts its positive affect
on ENaC activity through phosphorylation-dependent inhibition of Nedd4 –2 (263, 364; see Fig. 6).
In summary, loss of function of sodium transporters
tends to have more severe consequences, the more distally the loss occurs, despite the fact that, in absolute
terms, the distal transporters account for a small proportion of overall sodium reabsorption. This may reflect the
loss of compensatory capacity; there are no more lines of
defense for the body to fall back on (295).
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MULLINS, BAILEY, AND MULLINS
FIG. 9. A: renin angiotensin system. B: effect of AGT
copy number on angiotensin II concentration. C: effect of
ACE copy number on angiotensin II concentration.
Physiol Rev • VOL
potential pleiotropic effects of the mouse renin transgene.
When the transgene was crossed onto a new genetic
background, the animals were found to exhibit symptoms
of malignant hypertension (sudden rapid increase in blood
pressure followed by death). Subsequent breeding onto
Lewis and Fischer backgrounds led to the mapping of modifier loci on chromosomes 10 and 17, at or near the Ace and
the AT1 (Agtr1) loci, respectively, which affect susceptibility to malignant hypertension (154). The inducible MH
model is proving valuable for studying the transition to
hypertension and for discerning the pattern and reversibility
of end-organ damage in this model of hypertension (153).
Transgenic rats expressing rat prorenin exclusively
to the liver developed heart and renal pathology independent of hypertension, suggesting that prorenin may play a
role in development of vascular damage (362). Transgenic
rats harboring either the human renin gene or the human
angiotensinogen gene do not develop hypertension, because there is strict species specificity in the reaction
between renin and angiotensinogen (115). The double
transgenic strain reconstitutes an enzymatically functional RAS (86) and has proven a useful experimental
model for studying human-specific enzyme kinetics and
drug development.
Knockout of the Ren2 gene in a two-renin gene
mouse strain (129/Ola) has no discernible effect on blood
pressure (309). On the other hand, knockout of Ren1 in a
two renin-gene strain causes reduction of blood pressure
in females (56), together with characteristic changes in
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one renin gene (Ren1c), whereas others, such as DBA2/J
and 129, contain two (Rendc and Ren2d). The cardiovascular and renal phenotypes of one and two renin gene
strains have been extensively studied (199), as have their
differential patterns of gene expression (317). The renin
locus exemplifies natural variation among inbred strains
(214, 289).
The Ren2 transgene was cloned from the 129/Ola
strain of mouse, and the first direct demonstration of its
effect on blood pressure was its introduction into the rat,
which developed fulminant hypertension by 8 wk of age
(232). This was surprising, given that the same transgene
introduced into a single renin-gene mouse (Ren1c) did not
cause hypertension and is a classic example of species
specificity. The specificity may arise from differences in
the kinetics of angiotensin cleavage by renin in the two
species (287, 347). In addition to end-organ damage (in
heart, mesentery, kidney, and brain), the hypertension is
characterized by unchanged or suppressed plasma concentrations of active renin, ANG I, ANG II, and angiotensinogen, but plasma prorenin levels are greatly increased. Although kidney renin is suppressed, mouse
Ren2 is expressed at high levels in the adrenal gland,
suggesting the involvement of extrarenal RAS in this
model. Treatment with ACE inhibitors and AT1 blockers
efficiently reduces the hypertension, suggesting that it is
mediated through ANG II.
This rat strain, together with an inducible-Ren2 rat
(153), has been extensively studied, to determine the
TRANSGENICS AND HYPERTENSION
2. Angiotensinogen transgenics
Genetic linkage between certain variants of the human angiotensinogen gene and essential hypertension
(T235 vs. M235; A-6 vs. G-6) is well established (132, 136).
The physiological significance of these variants was investigated in transgenic mice by targeting two haplotypes
[⫺6G/235Met (GM) and ⫺6A/235Thr (AT)], as a single
copy transgene, to the mouse hypoxanthine phosphoribosyltransferase locus. This allowed direct comparison of
the two haplotypes in vivo. Both transgenes exhibit similar transcriptional activity and produce similar levels of
hAGT protein in the plasma. When each line was bred to
Physiol Rev • VOL
mice expressing human renin, however, only mice carrying the GM haplotype showed a small but significant
increase in blood pressure and compensatory downregulation of renin expression, suggesting the haplotypes may
affect blood pressure regulation differently (64).
Transgenic mice carrying an additional rat angiotensinogen (Agt) gene have been shown to exhibit hypertension (because angiotensinogen is rate limiting in the
mouse, Ref. 162), whereas knockout of angiotensinogen
results in hypotension (340). A more elegant demonstration of the importance of angiotensinogen in blood pressure control is the titration of gene copy number through
the breeding of targeted gene disruption and gene duplication mouse mutants (see Fig. 9B) (160, 322). Gene
duplication was achieved by a modification of gap repair,
such that the gene, together with 5⬘- and 3⬘-flanking sequences, was tandemly repeated. All animals were genetically identical except for having zero, one, two, three, or
four copies of the angiotensinogen gene. Plasma angiotensinogen levels increase progressively from zero, in the
zero-copy animals, to 145% of normal in the four-copy
animals. [Steady-state Agt levels increase progressively,
but not linearly, with Agt gene copy number because the
endogenous and duplicated genes are not functionally
equivalent (160).] Mice of all genotypes are normal at
birth, but most null animals die before weaning. Surviving
homozygous null animals exhibit pathological changes in
the kidney. Blood pressures of one- to four-copy animals
show increases of ⬃8 mmHg per gene copy, establishing
a direct causal relationship between Agt genotype and
blood pressure in this species.
Interestingly, Agt(⫺/⫺) animals on a C57Bl/6 background can be rescued by saline injection for 7 days after
birth. Hydronephrosis develops by day 14, and polyuria
by day 30, and the mice are chronically hypotensive.
Agt(⫺/⫺) pups born to Agt(⫺/⫺) mothers develop fetal
hydronephrosis and die of respiratory failure at birth
(339), suggesting that maternal RAS may affect structural
maturation of fetal kidney and lung.
Major sites of angiotensinogen expression include
the liver, kidney, and adipose tissue (64). A transgenic
model, with exon 2 of the human angiotensinogen gene
flanked by loxP sites, achieved tissue-specific ablation of
angiotensinogen using the Cre-loxP recombinase system
(delivered by intravenous administration of adenovirus,
which mainly infects the liver). A significant acute decrease in circulating angiotensinogen was achieved,
within 5 days, paralleled by a fall in blood pressure in
animals also carrying the human renin gene (327).
A transgenic model with overexpression of Hsd11b1
(which activates deoxycorticosterone to corticosterone),
specifically targeted to adipose tissue (211), exhibited
hypertension, in addition to classic symptoms of metabolic syndrome (visceral obesity, hypolipidemia, insulin
resistance, and glucose intolerance). The increased local
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morphology of the macula densa, and loss of granulation
in the juxtaglomerular cells of the kidney. All aspects of
the phenotype can be rescued by the introduction of a
wild-type BAC carrying Ren2 and Ren1, but not by a BAC
in which Ren1 has been insertionally inactivated with a
reporter construct before microinjection (234). Knockout
of Ren1 in a single renin-gene strain reduces viability,
with 80% of the pups dying within a few days of birth,
from dehydration. Survivors show significant lowering of
blood pressure (20 –30 mmHg); undetectable levels of
plasma renin, ANG I, and ANG II; increased urine and
drinking volume; reduced urinary aldosterone; and altered renal morphology (337, 386). Heterozygous Ren1c
⫹/⫺ mice are indistinguishable from wild type. In the dual
renin knockout, vascular hypertrophy is evident (213).
Placement of the GFP reporter downstream of a 4-kb
Ren1c promoter visualizes expression patterns of renin in
mouse embryonic, extraembryonic, and adult tissues
(144, 179). Such reporter constructs can also help to
identify short-range control elements (259, 260, 266). The
use of much larger transgenes, such as the 160-kb PAC
containing the human renin gene (321), have allowed the
identification of numerous potential control element binding sites upstream of the renin gene. Detailed analysis of
the expression patterns of all genes encoded within the
PAC has hinted at the location of longer range locus
control elements (241). Three-way sequence comparisons
between mouse, rat, and human (90) should confirm those
enhancer sequences and transcription factor-binding sites
that are conserved between species and are likely to be of
major physiological significance.
Transgenesis has been used to address the relative
contributions of endocrine and paracrine RAS (181). Recently, animals expressing both human renin and angiotensinogen, specifically in the proximal tubule under an
androgen-regulated promoter, were reported to have increased blood pressure following testosterone treatment
(67, 180). This is clear evidence that tissue-specific RAS
can contribute to the regulation of systemic blood pressure (115). The subject of brain RAS activity remains
contentious and is reviewed elsewhere (17, 230).
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3. ACE
The Ace gene might be considered a good candidate
for involvement in essential hypertension, because ACE
inhibitors are effective drugs for the treatment of high
blood pressure. Also, in humans, a common polymorphism in the ACE gene is associated with a quantitative
difference in ACE plasma levels (280). When a gene titration experiment was carried out on the Ace gene, plasma
ACE levels increased from 65 to 165% of wild-type levels
in one- and three-copy animals, respectively (170), although blood pressure was unaffected by the threefold
range in plasma ACE activity (see Fig. 9C). Kidney renin
levels were only moderately increased in the one-copy
animals.
The apparent paradox between lack of effect of varying ACE levels on blood pressure, and the effectiveness of
ACE inhibitors in reducing blood pressure, can be explained because ACE is not rate limiting in the RAS
pathway (336, 338). Computer simulations confirm that
progressive increase in Agt gene copy number causes a
progressive increase in both ANG I and ANG II levels, and
likewise, a decrease in Agt causes a fall in ANG I and ANG
II. In the one-copy Ace animal, the conversion of ANG I to
ANG II falls, causing a build-up of ANG I, which enhances
ANG II production, since ACE is working well below its
Physiol Rev • VOL
Km. When ACE is inhibited, ANG I levels increase until
they reach a steady state, balancing production by renin
with degradation by clearance mechanisms. Further reduction of ACE activity will result in reduced ANG II
levels and reduced blood pressure (323).
Animals completely lacking ACE exhibited abnormal
renal vessels and tubules (120), and renin and angiotensinogen mRNA levels were inversely proportional to
Ace gene copy number (345). Studies on the SNGFR of
Ace knockout mice indicate that TGF is absent in ACEdeficient mice but can be restored by acute infusion of
ANG II (348). Deletion of the COOH terminus of ACE
generated mice with plasma ACE but completely lacking
tissue-associated ACE (76). These mice were incapable of
forming ANG II in the proximal tubule, had a marked
reduction in blood pressure, had deficiencies in the RAS
system, and lacked TGF. Blood pressure could be restored by ectopically expressing ACE in the liver, but TGF
response was still markedly reduced compared with wild
type (111). This again exemplifies the intimate connection
between TGF and tissue RAS.
4. ANG II receptor
The physiological actions of ANG II are elicited by
specific cell surface receptors, belonging to the large
family of G protein-coupled receptors. The receptors can
be divided into two pharmacologically distinct types: AT1,
which mediates the major actions of ANG II and is inhibited by compounds such as losartan, and AT2, which is
inhibited by compounds such as PD123177. In mouse, the
AT1 receptors are divided into subtypes AT1A and AT1B,
which show differential tissue distribution and regulation,
further modulating the effects of ANG II. Knockout of the
AT1A receptor (Agtr1a) gene in mice causes a drop in
blood pressure in both heterozygotes and homozygotes
(134). Blood pressure can be further reduced in the null
animals, by administration of losartan, suggesting that the
AT1B receptor can contribute to blood pressure regulation
in the absence of AT1A receptor (250). Animals null for the
AT1A receptor exhibited no TGF response (300) and
showed hypertrophy of the JGA (254). Animals doubly
homozygous for Agtr1a and Agtr1b knockout have a phenotype similar to Agt knockout and the Ace knockout,
with reduced growth, vascular thickening within the kidney, atrophy of the inner renal medulla, reduced blood
pressure, and, additionally, no systemic pressor response
to ANG II infusion (253, 350). Paradoxically, administration of ACE inhibitor to these animals causes an increase
in blood pressure, suggesting that the AT2 receptor opposes the actions of AT1 receptors on blood pressure.
In Agtr1a knockout animals, the already low blood
pressure falls even further on a low-salt diet, and their
sodium balance becomes negative despite a sixfold increase in urinary aldosterone, indicating that the AT1A
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glucocorticoid levels cause an increase in angiotensinogen and ANG II, which ultimately raises blood pressure.
Interestingly, a related transgenic mouse, with Hsd11b1
targeted to the liver, exhibited metabolic syndrome and
hypertension without obesity (262).
The effect of angiotensinogen gene titration on homeostatic compensation in other components involved in
blood pressure control has been investigated (161). Highthroughput molecular phenotyping, using RT-PCR to assess the tissue-RNA levels of 10 genes, revealed both
positive and negative responses. A twofold increase in Agt
leads to a threefold increase in aldosterone synthase expression in the adrenal gland and a twofold decrease in
renal renin expression. Feedback inhibition of renin by
ANG II is to be expected and represents a large compensatory adjustment. This is not sufficient to return blood
pressure to normal because of the ANG II-induced increase in aldosterone synthase. There does not appear to
be an effective mechanism for negative feedback on aldosterone synthesis with increased blood pressure. No
change in kidney levels of kallikrein 1 (Klk1) or endothelial
NO synthase (Nos3) was observed, nor was cardiac expression of natriuretic peptide A (Nppa) or adrenomedullin
(Adm) affected by Agt genotype. Even more detailed
investigation of the wide-ranging changes that occur in
any transgenic model could be achieved by microarray
analysis, which allows the mRNA expression profile of
thousands of genes to be assessed simultaneously (191).
TRANSGENICS AND HYPERTENSION
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clear distinction between systemic and renal AT receptor
contribution to blood pressure is apparent.
B. Natriuretic Peptides and Receptors
Natriuretic peptides (NP) are physiological regulators of cardiovascular and renal function. Atrial natriuretic peptide (ANP) and B-type natriuretic peptide
(BNP) are released from the atria and the ventricles,
respectively, upon stretching of the cardiac myocytes,
while C-type natriuretic peptide (CNP) is found mainly in
the brain and is thought to act as a neurotransmitter (37).
All three peptides are venous dilators, but ANP and BNP
also evoke natriuresis.
There are three NP receptor subtypes: NPA, at which
ANP is the most potent agonist; NPB, which preferentially
binds CNP; and NPC, which binds all NPs with equal
affinity. NPA and NPB, both coupled to guanylate cyclase
activity, have an overlapping distribution in the kidney,
vasculature, and brain. NPC, the most abundant NP receptor (⬎90%), lacks guanylate cyclase activity and functions as a clearance receptor (212). The high density of
NPC in the brush-border membrane of the proximal tubule ensures that filtered NPs are removed from the tubule fluid, and thereby protects the paracrine function of
renal NPs. Short-term administration of ANP/BNP reduces MABP by lowering cardiac output and total peripheral resistance. Cardiac output falls due to the combined
effect of hemoconcentration (i.e., ANP promotes a redistribution of plasma water into the interstitium, an intrinsically hypotensive event) and suppression of autonomic
reflexes that would normally promote a reflex tachycardia
to oppose a reduction in MABP (303). The reduction in
total peripheral resistance reflects both direct, cGMPdependent actions on smooth muscle (247) and indirect
relaxation due to inhibition of central sympathetic drive
(303). ANP/BNP also increase sodium and water excretion by altering renal hemodynamics and tubule sodium
reabsorption. (25). NPs cause relaxation of afferent arteriole and contraction of the efferent arteriole, thereby
increasing SNGFR and filtered sodium load. Additionally,
tubular sodium/water reabsorption is inhibited either directly (an inhibitory action on ENaC) or indirectly [antagonism of the effects of antidiuretic hormone (ADH) and
ANG II]. ANP also influences volume status through inhibition of both aldosterone and ADH secretion.
1. Natriuretic peptides
Targeted overexpression of ANP to the liver causes a
significant reduction in blood pressure (328), indicating
that diuresis and natriuresis are not induced. Anp(Nppa)
⫺/⫺ mice have pronounced left ventricular hypertrophy,
suggesting that ANP is an important modulator of cardiac
function (229). Additionally, homozygous null animals fed
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receptor is critical for modulating sodium handling (251)
and water excretion (252). The severity of kidney histopathology was found to be variable on a mixed genetic
background (129 and C57Bl/6), suggesting the presence of
genes that can substantially modify the phenotype of AT1A
receptor deficiency. Suitable backcrossing has led to the
identification of a modifier locus on chromosome 3, with
significant linkage to the development of renal vascular
lesions (182).
Gene titration of the Agtr1a gene locus, to yield
animals with three and four copies of the gene, has shown
that AT1A mRNA and ANG II binding capacity increase in
proportion to copy number (182). In females (but not in
males), there is a strong positive correlation between
Agtr1a gene copy number, blood pressure, and AT1A receptor expression, a significant increase in aldosterone
synthase, a positive correlation between kallikrein and
AT1A receptor mRNA levels, and an inverse correlation
with renin mRNA.
The AT1 receptors are expressed in many tissues,
making it difficult to discern their role in particular sites
such as the kidney. An elegant strategy to overcome this
problem has utilized microsurgery for kidney transplantation between Agtr1a-knockout and wild-type mice (62).
Four groups of mice consisted of wild-type donors and
recipients (D⫹R⫹), wild-type donors and knockout recipients (D⫹R⫺), knockout donors and wild-type recipients
(D⫺R⫹), and knockout donors and recipients (D⫺R⫺).
Animals in the D⫹R⫹ group had normal blood pressure,
whereas the D⫺R⫺ group showed a 35-mmHg reduction
in blood pressure. Animals in groups D⫺R⫹ and, more
surprisingly, in the D⫹R⫺ group showed a 20-mmHg
reduction in blood pressure, clearly demonstrating that
regulation of blood pressure by the RAS is mediated, to
approximately equivalent extents, by both kidney and
systemic specific AT1 receptors. As aldosterone levels are
unaffected in the D⫺R⫹ group, reduction in BP in this
case is probably due to the lack of AT1A receptor action
on renal vasculature and/or epithelia (which would normally reduce urinary sodium excretion). Urinary aldosterone levels in the D⫹R⫺ group were ⬃50% of wild type,
but aldosterone replacement failed to restore blood pressure, suggesting that a lack of AT1A receptors in the
vasculature may account for the reduction in blood pressure in this group. Only groups D⫺R⫺ and D⫺R⫹ were
found to be sensitive to a high-salt diet, indicating that salt
sensitivity was associated with a lack of renal AT1A receptors. The contribution of AT1A receptors in the central
nervous system could not be assessed in this study, because kidney transplantation reduced sympathetic innervation in all groups. However, the marked (10-fold) increase in renin mRNA levels in the D⫺R⫺ group suggests
that below a certain blood pressure, a baroreceptor mechanism stimulates renin production (62). In summary, a
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2. Natriuretic peptide receptors
Knockout of NPC increases the half-life of ANP, and
both heterozygotes and homozygotes have a reduced ability to concentrate urine, mild diuresis, and depleted blood
volume. The homozygous animals are mildly hypotensive
(and unexpectedly have skeletal deformities).
Knockout of the NPA gene (Npr1) results in chronic
hypertension, which is insensitive to ANP infusion and is
salt resistant (194). These mice also have a blunted pressure natriuresis response (163). Gene titration of NPA
levels, generating animals with one to four copies of the
gene, demonstrate that below normal Npr1 expression
leads to a salt-sensitive increase in blood pressure,
whereas above normal Npr1 expression lowers blood
pressure and protects against high dietary salt (249).
Assessment of the RAS in zero-, one-, and two-copy
male mice suggests subtle interactions between NPA and
renin (311). Following blood volume expansion, the zerocopy mice show blunted increases in urinary flow and
Na⫹ excretion responses, despite increased arterial pressure, compared with nontransgenic controls, while fourcopy animals augment these responses and also have an
increased GFR and renal plasma flow (312). The only
association between natriuretic receptor peptide clearance genes and hypertension in humans has been shown
for a novel promoter variant of NPC. The variant was
associated with lower ANP levels and higher blood pressure in obese hypertensives (292).
3. Guanylin and uroguanylin
Guanylin and uroguanylin are synthesized in the intestine and kidney and appear to function as intestinal
natriuretic hormones (stimulating cGMP production via
guanylate cyclase C). Ablation of uroguanylin gene expression resulted in impaired ability to excrete an enteral
load of NaCl, due to an inappropriate increase in renal Na
absorption. The knockout animals were also found to
have increased blood pressure (196). Uroguanylin may
complement the renal effects of the cardiac natriuretic
Physiol Rev • VOL
peptides, through suppression of the TGF, although its
effects on glomerular microcirculation are far less than
those of ANP (373).
It would be interesting to see the effect of targeted
knockout of NPs or their receptors in the kidney, to
directly assess their systemic versus renal paracrine functions.
C. Endothelin System
The endothelin (ET) system involves the actions of
three peptides, ET-1, ET-2, and ET-3, on two G proteincoupled receptors, ETA and ETB (188). Endothelins are
formed from large peptide precursors, by endothelin converting enzyme (ECE), in a variety of cell types. ET-1 and
ET-3 are detectable in plasma whereas ET-2 appears to be
an intrarenal peptide. Both receptors have an extensive
distribution, but ETA predominates in the heart and kidney.
A role for the endothelins in blood pressure homeostasis is advocated by studies in healthy humans in
which nonselective receptor antagonism reduces MABP.
Receptor antagonism also normalizes blood pressure in
various forms of human and experimental hypertension.
A polymorphism in ET-1 has been associated with blood
pressure levels in overweight people (346).
The receptors are generally coupled to the activation
of phospholipase C (PLC), leading to an increase in intracellular calcium. Activation of ETA receptors leads to
vasoconstriction, cell proliferation, and matrix deposition. Activation of ETB receptors on endothelial cells
leads to release of PGI2 and NO, which inhibit ET-1 synthesis in the vascular wall, by a cGMP-dependent mechanism. ETB receptor activation thus offsets the vasoconstriction of ET-1, but ETB does elicit vasoconstrictive
actions on the renal circulation.
Administration of ET-1 into the renal artery causes
profound, long-lasting vasoconstriction of the renal circulation, and depression of renal blood flow and GFR
(through constriction of the afferent arteriole), leading to
reduced renal sodium excretion. The renal circulation is
particularly sensitive to vasoconstrictive actions of ET.
This has important ramifications for both physiology and
pathophysiology since subthreshold levels of ET can sensitize the renal vasculature to the actions of other vasoconstrictors (167). ET-1 is secreted by proximal tubular
cells, and microinjection of ET-1 into the proximal tubule
lumen, and/or exposure of the macula densa to ET-1,
caused a significant increase in SNGFR (286). This may
reflect a physiological mechanism for activating the TGF.
Intrarenal, paracrine endothelins, synthesized in the collecting duct, promote renal salt loss through activation of
renal epithelial ETB receptors and may play a substantial
role in blood pressure homeostasis (1). Although systemic
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a normal-salt diet have increased blood pressure, and
plasma catecholamine concentration is significantly elevated in these mice (222). On a high-salt diet, heterozygotes become hypertensive, indicating that genetically
reduced ANP can lead to salt-sensitive hypertension
(140). Salt sensitivity in the ⫺/⫺ mice is associated with
failure to downregulate plasma renin activity (223), and daily
losartan treatment reduces arterial blood pressure and catecholamine levels to normal, suggesting an interaction between ANG II and sympathetic nerve activity (222). Mice
lacking corin, the enzyme required to process proANP, also
have no detectable ANP, and adult mice have chronic hypertension, cardiac hypertrophy, and an exaggerated pressor response to salt loading and pregnancy (48).
TRANSGENICS AND HYPERTENSION
Physiol Rev • VOL
D. Nitric Oxide Signaling Pathways
The potent vasodilator NO, produced from the oxidation of L-arginine by NO synthase (NOS) enzymes, regulates a wide variety of cardiovascular and renal functions and is important in both the short- and long-term
control of blood pressure (376). Three different forms of
the enzyme have been identified: endothelial (eNOS or
type 3), neuronal (nNOS or type 1), and inducible (iNOS
or type 2) (226), which are differentially expressed in the
cardiovascular system and the kidney. Mice with targeted
disruptions in each of the Nos genes have been used to
provide insights into the role of NO in blood pressure
homeostasis (255).
Overexpression of eNOS leads to hypotension and a
reduced response to the endothelium-derived relaxing
factor NO (246). Mice lacking eNOS are hypertensive
(174, 326), partly due to the lack of constitutively active
NO, which favors vasoconstriction and leads to an apparent increase in sympathetic tone. Pharmacological inhibition of NOS activity also augments sympathetic-induced
vasoconstriction (165, 365), and eNOS (Nos3) null mice
have an increased basal vasoreactivity in the pulmonary
circulation and markedly elevated, hypoxia-mediated vasoconstriction (77). Inhibition of nNOS or iNOS fails to
exacerbate hypertension in Nos3 null mice (164), indicating that there is little compensatory NO production. In
fact, selective inhibition of nNOS, either chronically or
acutely, evokes a marked reduction in MABP in eNOS
knockouts, suggesting that nNOS has a basal pressor
action (174). This apparent paradox can be explained by
the fact that NO derived from central nervous system
nNOS facilitates sympathetic nerve activity (215, 220) and
exerts a permissive effect on the baroreceptor reflex (70).
An attenuated baroreceptor reflex in eNOS knockout
mice means they do not elevate heart rate after L-NAMEinduced hypotension (174). Aortic rings, taken from eNOS
null mice (126), and to a lesser extent heterozygous mice
(79), fail to relax in response to acetylcholine (ACh). The
response is restored by transfection with a viral vector
carrying the eNOS gene (307), indicating that in large
vessels, eNOS mediates ACh-induced vasodilation.
In the kidney, eNOS is expressed in the vasculature
and in several segments of the tubular epithelium. Although NO profoundly influences renal circulation, Nos3
null mice maintain renal blood flow (23), due to compensatory vasodilators. In the proximal tubule, eNOS-derived
NO exerts a basal inhibition of Na⫹ reabsorption (3),
although this is not a consistent finding (372). Plasma
renin activity is either normal (23) or inappropriately
elevated (310) in Nos3 ⫺/⫺ mice, given the high blood
pressure. Renin mRNA in the kidney, however, is consistently decreased (310, 366). The substrate for NOS, Larginine, decreases NaCl absorption by the TAL. Gene
transfer of Nos3 (by recombinant adenovirus vector) to
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endothelin concentration does not correlate well with
either the development or degree of hypertension, the
renal excretion of ET-1 (reflecting renal synthesis) does,
at least in DOCA-treated rats.
Transgenic mice overexpressing ET-1 are normotensive (suggesting counterregulatory compensation) (121),
but chronic overproduction of ET-1 leads to pathological
changes in the kidney (consistent with matrix deposition), increased urinary protein excretion, and salt sensitive hypertension (316). When the NO system is antagonized with NO synthase inhibitor (L-NAME) vascular contraction is reduced, indicating its involvement in the ET-1
transgenic phenotype (275).
ET-1, ECE, and ETA knockout mice have craniofacial
abnormalities and die at birth. Animals heterozygous for
the ET-1 (Edn1) null allele are mildly hypertensive (175),
reflectinglong-termhypoxia,adisturbanceincentralcardiorespiratory regulation, or an ETA/ETB imbalance. [ETB
(Ednrb) ⫹/⫺ animals have raised blood pressure, which
is restored to normal by ETA inhibitors (28).] A high-salt
diet significantly reduces renal ET-1 levels but does not
induce salt sensitivity in the ET-1 heterozygous knockout
(231). Renal sympathetic nerve activity in anesthetized
mice is higher in Edn1 (⫹/⫺) mice than in wild-type mice,
suggesting that ET-1 normally participates in this reflex
and that the baroreceptor is reset at a higher level in
ET-1-deficient animals (193).
Cre-lox technology was used to overcome ET-1
knockout lethality, targeting gene deletion to the collecting duct (5). Plasma ET-1 levels were normal in these
mice, but urinary excretion of ET-1 was significantly reduced, consistent with a separation of the systemic and
renal endothelin systems. On a normal-salt diet, ⫺/⫺ mice
were hypertensive, but renal sodium handling and plasma
renin activity were normal. Salt loading exacerbated the
hypertension through renal sodium retention, which was
ameliorated by amiloride. Since control mice doubled
their renal excretion of ET-1 during salt loading, and the
⫺/⫺ animals did not, this strongly implicates collecting
duct ET-1 synthesis in the normal response to sodium.
Cre-lox technology has also been used to target ETA
knockout to the heart. Animals develop normally and
show normal stress-induced responses to ANG II (158).
Likewise, ETB receptor knockouts can be rescued from
neonatal lethality by expression of a dopamine ␤-hydroxylase promoter/ETB receptor transgene. Studies on acid
balance and NHE3 levels suggest that metabolic acidosis
increases ET-1 expression, which increases NHE3 activity
via the ETB receptor (176). Rats carrying a natural deletion of ETB have similarly been rescued and exhibit severe hypertension on a high-salt diet (87). In summary,
transgenic models have provided a clear distinction between systemic and renal endothelin functions.
729
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MULLINS, BAILEY, AND MULLINS
E. Kallikrein-Kinin System
Evidence for the importance of the kallikrein-kinin
system (KKS) in long-term blood pressure regulation
comes from epidemiological studies in which genetically
reduced kallikrein activity was associated with the development of high blood pressure even before the onset of
clinical hypertension. This suggests an intact KKS may be
required to avoid hypertension when additional risk factors are present.
The KKS is a multienzyme system consisting of the
substrate kininogen, the activating enzyme kallikrein, and
active metabolites, of which bradykinin is predominant
(see Fig. 10). The substrate kininogen is encoded by a
Physiol Rev • VOL
FIG. 10. The kallikrein-kinin system, showing formation, actions,
and breakdown products of bradykinin.
single gene (in humans), which produces two kininogen
products by alternative splicing. Plasma kininogen is synthesized primarily in the liver but also by platelets, neutrophils, and endothelial cells (31). Tissue kininogen, the
lower molecular weight product, is synthesized in the
peripheral tissues, notably in the kidney, where it is localized to the collecting duct.
Kallikreins are also produced in two main forms,
plasma and tissue kallikrein. Tissue kallikrein (TK), the
major kinin-forming enzyme, is expressed in a variety of
systems, most notably in the distal nephron of the kidney.
The effective colocalization of both kininogen and kallikrein in the distal nephron permits the local, extracellular production of bradykinin in either blood or urine (the
components of the KKS are secreted across both membranes). Since the plasma forms of kininogen or kallikrein
are not filtered at the glomerulus, the KKS in the kidney is
effectively isolated so that bradykinin excretion in the
urine reflects intrarenal production.
There are two bradykinin receptors, B1 and B2, but
most known physiological effects are mediated through
the B2 receptor: B1 receptor expression is largely induced
by tissue injury or inflammation. Kinins are rapidly inactivated by ACE (kininase II) and neutral endopeptidase.
The KKS mediates both inflammatory and constitutive responses. During inflammation, plasma KKS increases vascular permeability, leading to edema, and contributes to the fall in blood pressure associated with
sepsis. Tissue KKS operates constitutively, controlling
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the TAL of Nos3 ⫺/⫺ restores L-arginine-induced inhibition of NaCl transport (256), confirming the importance of
eNOS in this process.
Animals lacking eNOS also exhibit insulin resistance
and hyperlipidemia, indicating that eNOS may represent a
link between metabolic and cardiovascular disease (73).
Under normal conditions, Nos3 heterozygotes are normotensive, but they have an accelerated hypertensive response to a high-fat diet (59). The link between eNOS and
the metabolic syndrome is further supported by a significant linkage between two polymorphisms in the NOS3
gene and the metabolic syndrome (82). In addition, male
Nos3 ⫺/⫺ mice have a markedly reduced life span and
develop pronounced cardiac dysfunction with age (190).
The reason for this sexual dimorphism is unclear, but
recent data suggest that endothelium-derived hyperpolarizing factor (EDHF), rather than NO, is the predominant
relaxing factor in female mice (306).
Blood pressure in nNOS knockout mice is normal
(238, 357), suggesting that NO derived from this source
plays only a minor role in BP management or can be fully
compensated for by other vasodilators. In the kidney,
nNOS is expressed in the collecting duct and TAL but the
highest expression is in the cells of the macula densa,
consistent with the known modulatory role of NO on
renin release, afferent arteriolar tone and TGF. Despite
this, TGF is normal in Nos1 null mice (357), and renal
renin levels are comparable to wild type (366).
Although the Nos2 gene is linked with blood pressure
in Dahl salt-sensitive rats, its role is unclear. In knockout
mice, early hypertension disappears as the mice reach
adulthood, and salt loading has no adverse effect (130).
Constitutive expression of iNOS is observed in the kidney,
especially in the proximal tubules. It remains unclear
whether iNOS-derived NO has an inhibitory (106) or stimulatory (372) action on sodium reabsorption. Clearly,
more studies are required to reveal the complex relationships between NOS isoforms, NO, and blood pressure
control.
TRANSGENICS AND HYPERTENSION
1. Kallikreins
Kallikrein levels are lower in nonmodulating hypertensives than modulating hypertensives or controls (291).
Additionally, patients with a loss-of-function polymorphic
variant of the human tissue kallikrein gene exhibit arterial
dysfunction (15). To assess the role of the kallikrein-kinin
system in blood pressure control, human tissue kallikrein
was introduced into mice, under the metallothionein promoter. Transgene expression was identified in the pancreas, salivary gland, kidney, liver, and spleen, and animals had significantly reduced blood pressure (370),
which was restored to normal by administration of the
kallikrein inhibitor, aprotinin. Human tissue kallikrein has
been used for gene therapy in several hypertensive rat
models, including the Goldblatt hypertensive rat (389),
the SHR (392), and the fructose-induced hypertensive rat
(393). In all cases, hypertension was significantly reduced.
Tissue kallikrein-deficient mice are unable to produce
kinins and have marked cardiovascular abnormalities
(224). Despite this, blood pressure is normal. The flowdependent vasodilation of resistance vessels involves TK
production of bradykinin, which is attenuated in TK
(Klk1b1) ⫺/⫺ mice (26). Kinins have been implicated in
the beneficial effects of ACE inhibitors (318).
In a rat model bred for low kallikrein levels (LKR),
kallikrein was reduced by 60% in the kidney (although it
was increased in the heart and unaltered in pancreas,
liver, and salivary glands). LKR exhibited an increased
mean arterial blood pressure, polyuria, glomerular hyperfiltration, and reduced sodium excretion, and renal vasodilation in response to volume expansion was impaired.
The phenotype was attenuated by AT1 blockade, suggesting that a balance between the KKS and the RAS is
essential for normal renal function (203). One should
remember that animal models bred for a specific phenotype may carry contributing variants at a number of loci.
Physiol Rev • VOL
2. Kinin receptors
The effect of bradykinin B2 receptor (Bdkrb2) knockout is contentious. Some groups found a mild increase in
blood pressure in knock-out mice (202), while others
found that knockout animals on a normal salt diet had
normal blood pressure (10). Both null animals and those
heterozygous for the knock-out allele show exaggerated
vasopressor responses to ANG II (202). Null animals show
increased sensitivity to deoxycorticosterone, with a more
rapid and pronounced increase in blood pressure than
controls (75), and increased sensitivity to high-salt diet
hypertension, with renal blood flow reduced by 20%, and
renal vascular resistance doubled compared with a normal-salt diet (9), indicating a tonic vasodilatory effect of
bradykinin in this vascular bed. Salt-sensitive hypertension can be reversed by selective ETA and ETB antagonists, and also by inhibitors of ACE and AT1 receptors,
suggesting that ET-1 and ANG II are involved in the
development of hypertension (39).
The antidiuretic effect of arginine vasopressin in B2
receptor null mice is also enhanced (8), suggesting that
endogenous kinins act through the B2 receptor to oppose
the effects of arginine vasopressin in vivo. ACE inhibition
leads to increases in bradykinin, COX-2, and renin, suggesting that renin may be regulated through a kinin-COX-2
pathway. In B2 receptor knockout mice, renal COX-2 levels are reduced by 40 –50% and renal renin levels by 60%,
but other components of the RAS remain unchanged
(131). Blockade of the AT1 receptor in B2 receptor knockouts prevents the cardiac remodeling seen in this model,
suggesting that interaction between ANG II and bradykinin is important for normal heart development (201). A
deletion polymorphism of human B2R gene has been
associated with exaggerated cardiac growth response to
physical exercise (42). In a transgenic model overexpressing the B2 receptor, the animals develop chronic hypotension. Urine volume, K⫹, and pH are all increased, but
Na⫹ excretion is unaltered. The animals exhibit enhanced
renal function, with increased renal blood flow, GFR, and
urine flow. Significant increases in urinary nitrate, cGMP,
and cAMP suggest that the enhanced renal function is
achieved via activation of the NO signal transduction
pathway (369).
In summary, the noted hypotensive actions of the
KKS relate to effects on both renal hemodynamics and
tubular sodium reabsorption. Transgenic approaches
have demonstrated that the KKS interacts with a variety
of separate vasoactive systems. Among these, an interaction with the RAS is of particular clinical significance.
ACE inhibition will increase bradykinin levels, the effects
of which are uncertain. On the one hand, the natriuretic
effect of bradykinin would be beneficial in the treatment
of hypertension; on the other hand, bradykinin can induce
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organ perfusion by evoking vasodilation in the myocardium, kidneys, and other microvascular beds, via increases in endothelial mediators such as NO, cGMP, and
prostacyclin (see Fig. 10). Although kinins cause vasodilation of both the afferent and efferent arterioles, the
effect on the afferent is more pronounced, and GFR is
thus increased. Bradykinin also increases blood flow in
the renal medulla through complex interactions with vasoconstrictors such as ANG II (351).
Systemic administration of bradykinin evokes,
through activation of B2 receptors, natriuresis and diuresis. This relates both to inhibition of sodium reabsorption
in the segments of the medullary collecting duct and
reduced medullary hyperosmolarity as a consequence of
increased vasa recta blood flow. Bradykinin exerts actions at the JGA, reducing the sensitivity of the TGF
response and directly stimulating renin release.
731
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MULLINS, BAILEY, AND MULLINS
a marked fall in GFR, thereby attenuating the salt-shedding impact of ACE inhibition (81).
F. The Dopaminergic System
FIG. 11. Action of dopamine on sodium transport in the proximal
tubule. Dopamine, acting via D1 receptors, inhibits both the apical
sodium-hydrogen exchanger (NHE3) and the basolateral Na⫹-K⫹-ATPase.
Physiol Rev • VOL
G. Cyclooxygenase Pathway of Arachidonic
Acid Metabolism
Arachidonic acid is metabolized into its active products, the eicosanoids, by three distinct enzyme pathways
(see Fig. 12). COXs produce prostaglandins and thromboxanes; lipoxygenase gives rise to hydroxyeicosatetraenoic acids (HETEs), the leukotrienes, and lipoxins; and
cytochrome P-450 (CYP450) produces 20-HETE and the
epoxyeicosatrienoic acids (EETs). All of these active
products can modulate hemodynamics and renal salt homeostasis and therefore have the potential to regulate
blood pressure. Although genetic modification has been
used to interfere with parts of this pathway, most of these
models have been directed toward studies of inflammation, rather than blood pressure regulation, and will not
be considered in this review.
The importance of COXs in the control of blood
pressure is illustrated by the use of nonsteroidal antiinflammatory drugs in humans, which inhibit both COX
isoforms (COX-1 and COX-2), cause Na⫹ retention and
hypertension (51), and interfere with the efficacy of ACE
inhibitors (13). Additionally, COX-2 expression is stimulated by ACE inhibitors and low salt (47, 149). COX-1 is
constitutively expressed in a variety of tissues, including
the kidney. The exact function of renal COX-1 remains
uncertain: the gene does not appear to be dynamically
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Dopamine, better known as a neurotransmitter, can
act as a hormonal modulator of blood pressure and is
implicated in hypertension on the basis of studies in
humans and rodent models (391). Dopamine produced by
the kidney in response to increased Na⫹ loading is an
intrarenal regulator of sodium transport. It acts through G
protein-coupled receptor(s) in renal proximal tubules to
effect natriuresis through the inhibition of apical NHE3
and basolateral Na⫹-K⫹-ATPase (see Fig. 11). Kidney cell
experiments suggest that signaling cascades downstream
of the dopamine D1 receptor include adenyl cyclase protein kinase A-dependent phosphorylation followed by
PLC- and protein kinase C-␨-dependent phosphorylation
(93, 94), which ultimately leads to the inactivation of the
major Na⫹ transporters. Dopamine-induced reduction of
Na⫹-K⫹-ATPase occurs through endocytosis, while recruitment to the plasmalemma, induced by serotonin or
the phorbol ester phorbol 12-myristate 13-acetate (via
protein kinase C-␤-dependent phosphorylation), leads to
an increase in Na⫹-K⫹-ATPase activity (43, 74). The relative balance between activation or inactivation of Na⫹K⫹-ATPase appears to be controlled by intracellular Na⫹
concentration (74).
In mice lacking one or both copies of the D1 receptor,
both systolic and diastolic blood pressures are increased
(7). In SHR rats, in spite of normal dopamine production
and receptor density in the kidney, defective transduction
of the D1 receptor signal results in decreased inhibition of
sodium transport. The defective coupling between D1 receptor and its G protein/effector enzyme complex is due,
at least in part, to excessive serine phosphorylation of the
receptor by a mutant G protein-coupled receptor kinase
(GRK). The GRK4 locus has been linked with human
essential hypertension (145), and several SNPs have been
identified (271). Of these, the GRK4␥A142V SNP has the
greatest effect on D1 function in vitro. Transgenic mice
expressing this variant were hypertensive and showed
impaired diuretic and natriuretic, but not hypotensive,
effects of D1 agonist stimulation (80).
The D3 receptor is expressed in the proximal tubules
and the juxtaglomerular cells and also appears to affect
natriuresis and diuresis. Knockout of D3 receptor increases systolic and diastolic blood pressures and renal
renin activity and causes sodium retention (12). The increased urine flow rate and Na⫹ excretion associated
with acute salt loading are attenuated in the homozygous
null animal.
The dopamine receptor D5 is also involved in blood
pressure control, since its knockout results in significant
hypertension by 3 mo of age (122). The hypertension
appears to be caused by increased sympathetic tone,
mediated through a central nervous system defect.
TRANSGENICS AND HYPERTENSION
733
FIG. 12. Major pathways of arachidonic acid metabolism in the kidney.
Physiol Rev • VOL
expressed Ren2 gene, which may not be affected by Ptgs2
deletion.
Although PGE2 is a major product of COX, PGE2
receptor null mice (Ptger2 null) have no gross abnormalities, and blood pressure is normal. They do lose the
hypotensive response to intravenous PGE2 infusion (although ability to vasodilate is inherently normal) and
develop a marked hypertension on a high-salt diet (159).
H. Other Potential Contributing Factors
The general usefulness of ␣- and ␤-blockers in reducing blood pressure points to the involvement of adrenergic receptors in blood pressure control and their inclusion
as candidate genes. There are nine adrenergic receptor
subtypes (three ␣1, three ␣2, and three ␤), and the lack of
selective pharmacological agents means that transgenic
and knockout strategies have been very useful in distinguishing the various roles of the receptors (see Table 1).
The ␣1-adrenoceptors (ARs) are postsynaptic receptors,
which mediate some of the main actions of the catecholamines, epinephrine and norepinephrine, and play a
crucial role in blood pressure regulation. The ␣2-AR are
largely presynaptic and distributed in the central nervous
system, although they are the numerically predominant
AR type in the kidney. The ␤-AR appear to cross-compensate for each other, since mice with a single knockout of
each have normal resting blood pressure and response to
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regulated by alterations in salt and water intake, and
COX-1 (Ptgs1) knockout mice display neither renal abnormalities nor misregulation of blood pressure (177).
COX-2 has a more restricted distribution, being limited in the kidney to the thick limb of Henle and cells of
the macula densa. Expression of COX-2 is dramatically
upregulated, at both the mRNA and protein level, by
low-salt diet intake, consistent with its key role in the
stimulation of renin release. Knockout of COX-2 (Ptgs2) is
associated with decreased renin synthesis and granularity
in juxtaglomerular cells, which does not increase on a
low-salt diet (387) or in response to ACE inhibition (52).
Ptgs2 knockout mice also display a marked but variable
renal pathology, featuring glomerular hypoplasia and tubular atrophy (71, 228), yet blood pressure regulation in
the Ptgs2 mice is normal. In both of these studies, the
gene deletion was on a mixed C57/Bl6 and 129/Sv background. A backcross breeding strategy was used to introduce the Ptgs2 deletion onto 129/Sv, Balb/C, or C57/B6
congenic backgrounds (388). All strains displayed the
renal pathology, but the most severe phenotype was observed on the 129/Sv background in which the males also
developed a malignant hypertension. This demonstrates
that genetic background is an important factor in the
development of hypertension and can modify the severity
of a single gene disorder. The development of hypertension may be related to the RAS. Both C57BL/6 and BalbC
mice have the single Ren1C and the RAS would be expected to be suppressed following deletion of Ptgs2. Mice
from the 129/Sv strain have, in addition, the constitutively
734
MULLINS, BAILEY, AND MULLINS
TABLE
1.
Adrenergic receptor transgenics and their effects on blood pressure
Receptor
Transgenic Alteration
Effect on Blood Pressure
Reference Nos.
␣1A
␣1B
␣1D
␣2A
␣2B
␣2C
␤1
␤2
␤3
Knockout
Overexpression
Knockout
Knockout
Knockout
Knockout
Knockout
Knockout
Knockout
Hypotension
Hypotension
Hypotension
Increased resting BP
No response to salt load
Normal response to salt
Perinatal lethal; BP normal; no response to isoproterenol
Blunted response to isoproterenol
Blocks NO-dependent suppression of inotropy
285
397
125, 342, 343
117
205
205
284
54
359
BP, blood pressure; NO, nitric oxide.
TABLE
2.
VIII. PERSPECTIVE
We have noted, throughout our review, a number of
genes that exert their action both systemically and in the
kidney. It has long been held as the central tenet of
pressure natriuresis that the kidney is the seat of pressure
control (103); an increase or decrease in arterial pressure
will be matched by the appropriate excretion or retention
of sodium and water, to achieve long-term balance. A
clear demonstration of distinct kidney and systemic control mechanisms has been dramatically highlighted by the
kidney transplantation experiment of Crowley et al. (62),
which suggests that nonrenal tissues, such as the vasculature, may be potentially important contributors to blood
pressure control. Equally, factors such as ANG II may
contribute to vascular disease irrespective of their role in
blood pressure (66).
The above description of transgenic and knockout
strains is comprehensive but by no means exhaustive and
broadly exemplifies the transgenic strategies currently
available and the kind of questions that can be asked. The
importance of genetic background cannot be overstated;
Other factors reported to affect blood pressure in transgenic or gene targeting models
Gene
Tg/KO
Blood Pressure Change
Adrenomedullin
Adenosine receptor
A2aAR
A1AR
␤-Adducin
Parathyroid hormone-related protein (PTHrP)
PTHrP receptor
Orexins
E-prostanoid receptors (EP)
EP1
EP2 and EP4
Leptin
LDL-R
GLUT-4
Insulin receptor substrate-1
Thromboxane (TxA2)
Adenoviral gene delivery
Attenuates hypertension
KO
KO
KO
Overexpression
Overexpression
KO
Hypertension
Renin expression enhanced on low salt
Hypertension
Hypotension
Hypotension
Decreased basal arterial pressure
KO
KO
Overexpression
KO
Heterozygote
KO
KO
Decreased male vasopressor response to PGE2
Decreased female vasopressor response
Hypertension*
Hypertension*
Hypertension*
Hypertension*
Hypertension caused by ANG II infusion is attenuated
* Hypertension may be indirectly linked to underlying genetic alteration. KO, knockout; LDL, low-density lipoprotein.
Physiol Rev • VOL
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Reference Nos.
72, 368
183
305
210
204
274
157
14
245
349
329
2
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exercise. From analysis of these single knockouts, plus
double knockouts, it appears that all three ␤-ARs control
vascular relaxation (283). Interestingly, positional
genomic analysis has identified the ␤-AR gene as a susceptibility locus for human hypertension (36). Caution is
required in translating the wealth of information from
animal studies to the human situation, because of different expression patterns of the various receptor subtypes,
especially in the heart (341).
Numerous other genes have been shown to affect
blood pressure in transgenic or gene targeting models,
hinting at their possible involvement in essential hypertension. Several of these genes have been summarized in
Table 2 for the interested reader. The relationships between obesity, insulin resistance, and hypertension are
complex and beyond the scope of this review. Some
animal models are beginning to shed light on the interrelationships, although it is not always clear whether the
variation in blood pressure seen in any of these models is
directly or indirectly linked to the underlying genetic
alteration (41).
TRANSGENICS AND HYPERTENSION
Physiol Rev • VOL
culture of mouse spermatogonial stem cells (SSCs) for
periods in excess of 6 mo, opens up exciting possibilities
for germline modification (173) by this route. The stem
cells, generated from neonate, pup, and adult testes, can
be transplanted into recipient seminiferous tubules, after
extensive culture, and are able to reconstitute long-term
spermatogenesis, or even restore fertility to infertile recipients. In vitro proliferation of SSCs should make genetic manipulation, such as targeted modification, possible. Such strategies could prove invaluable for species,
such as the rat.
With the rapid advances in transgenic technology,
one can anticipate the introduction of increasingly sophisticated and subtle genomic alterations to understand the
genetic basis of hypertension. Equally exciting is the potential for applying knockout technology to alter genes in
classical animal models, such as SHR, in an attempt to
rescue the hypertensive phenotype.
Given the multigenic complexity of essential hypertension, computer simulations have an important role to
play in assessing the contribution of genes to overall
blood pressure. Making simple assumptions, one can begin to build ever more complex models, adding one enzyme at a time, building in pathways, and systems to
account for perturbations in the data seen in gene titration experiments (336). Such modeling may identify
groups of allelic variants or mutations, which given certain prenatal programming, or dietary or environmental
stimulation, will lead to the development of hypertension.
Identifying patients with similar predisposition will be
helpful in tailoring therapy or even prevention.
Rapid advances in functional genomics and proteomics mean that the majority of genes identified and mapped
in the whole genome sequencing programs will be classified and have functions assigned to them. Ultimately, it is
the interactions between gene products that mediate
physiological responses (361). The use of siRNAs to mediate gene-specific posttranscriptional silencing or knockdown is likely to prove an efficient method for studying
gene function in mammalian cells. Plans to conduct largescale screens on a genome scale should help to assign
both broad and specific functions to genes, in a highthroughput manner (109, 258, 319). There is a suggestion
that RNA interference could ultimately be used therapeutically (45), provided that techniques to allow efficient,
stable production and, more importantly, delivery to target tissues are refined (367).
Functional genomics and proteomics will greatly advance the ability to identify genes that are differentially
expressed in hypertensive and normal animals and/or
patients. The challenge will be to identify the functionally
relevant interactions that directly impact on essential hypertension.
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meaningful comparisons should only be made between
transgenics and appropriate controls. Equally, comparisons between transgenic lines should always be made on
the same genetic background, a requirement that is
readily attainable with the development of speed congenics (where parent choice for each generation is determined following detailed microsatellite analysis, to assess
the relative contribution of “parental” genomes). That
said, crossing onto an alternative genetic background may
reveal different subtleties of phenotype reflecting the
presence of modifier loci. These may prove important in
identifying or defining differences in susceptibility to hypertension in human populations. A note of caution: it is
not implicit that any given gene identified as having a role
in hypertension in the animal model will automatically be
involved in human essential hypertension. However,
genes identified as important in animals are potential
contenders for QTL or association analysis in patients and
may highlight relevance to essential hypertension in humans.
A lot can be learned from the generation of animals
carrying multiple mutations (compound heterozygotes),
either within a system or from different control pathways,
to determine how they interact in health and disease. By
introducing multiple components of human RAS into the
mouse or rat, one can study elements of the human pathway in physiological context, perhaps pharmacologically,
or investigate potential therapeutic interventions in the
animal models generated. This may be especially helpful
where species specificity means that the candidate gene is
not normally functional in a heterologous species.
The vast majority of gene knockout experiments
have been achieved in the mouse. Since a wealth of
knowledge has accumulated from the many rat models of
hypertension, it would be ideal to apply knockout technology to the rat.
One strategy for the production of knockout rats is
the use of ethyl-nitroso-urea (ENU) mutagenesis (390),
which randomly introduces point mutations into the genome through intercalation of ENU into the DNA. An
appropriate screening protocol is necessary to look for
mutations in genes of interest (390).
To date, the production of germline-competent rat ES
cells, for gene-targeting, has proven elusive. Two groups
have reported the culture of rat ES-like cells for many
generations (44, 360), making them available for transfection with targeting constructs. Recently, nuclear cloning
has been achieved using two-cell-stage embryos as donor
and recipient cells (282). It may be possible, in the future,
to use targeted ES-like cells as a source of nucleus for
nuclear transfer, thus circumventing the need for germline competence (235).
The identification of exogenous growth factors and
serum-free culture conditions, which allow continuous
735
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MULLINS, BAILEY, AND MULLINS
ACKNOWLEDGMENTS
Address for correspondence: L. J. Mullins, Molecular Physiology Laboratory, Cardiovascular Science Centre, Queens Medical Research Institute, Univ. of Edinburgh, 47 Little France
Crescent, Edinburgh EH16 4TJ, UK.
All mouse gene nomenclature is according to the Mouse
Genome Informatics website (http://www.informatics.jax.org).
REFERENCES
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