Circulation Mtesearch
FEBRUARY
1981
VOL. 48
NO. 2
An Official 'Journal of the American Heart A*MOeiation
BRIEF REVIEWS
Role of the Intrarenal Renin-Angiotensin
System in the Control of Renal Function
NIGEL R. LEVENS, MICHAEL J. PEACH, AND ROBERT M. CAREY
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IN THIS review article, we will assess the evidence
for the presence and the mechanism of the intrarenal renin-angiotensin system acting as a local
hormonal system in the control of renal function.
First, we will review the evidence for the presence
of a renin-angiotensin system in the kidney. Second,
using results of our own and other studies, we will
develop the concept that the intrarenal renin-angiotensin system acts as a local hormonal system in
the control of renal function. Third, we will discuss
experimental observations on the intrarenal effects
of angiotensin II. Fourth, we will evaluate the evidence for a direct renal tubular action of angiotensin
II. Fifth, we will assess the role of the intrarenal
renin-angiotensin system in renal autoregulation.
Finally, we will speculate on the function of the
intrarenal renin-angiotensin system in the regulation of fluid and electrolyte homeostasis in general.
Studies of the Localization of the
Intrarenal Renin-Angiotensin System
Localization of the Site of Renin Secretion
It now is almost universally accepted that the
enzyme, renin, is synthesized and stored by specialized cells, the juxtaglomerular cells, of the renal
afferent arteriole in intimate contact with the distal
tubule (Edelman and Hartroft 1961; Robertson et
al, 1965; Cook 1967; Johnston et al., 1973; Silverman and Barajas 1974; Davis and Freeman 1976).
The juxtaglomerular cells are thought to be modified smooth muscle cells because they contain bundles of fibrils and attachment bodies similar to those
of smooth muscle cells (Latta, 1973). The macula
densa consists of an elongated group of columnar
From the Division of Endocrinology and Metabolism, Department of
Medicine, and the Department of Pharmacology, University of Virginia
School of Medicine, Charlottesville, Virginia.
Dr. Levens is a recipient of a postdoctoral travel fellowship award
from the Wellcome Trust, England.
Dr. Carey is an Established Investigator of the American Heart
Association.
Address for reprints: Dr. Robert M. Carey, Box 482 University of
Virginia Medical Center, Charlottesville, Virginia 22908.
epithelial cells situated in the distal convoluted
tubule as it passes the glomerulus after it ascends
from the medulla (Latta, 1973). Collectively, the
macula densa, the juxtaglomerular cells, and the
afferent glomerular arteriole are termed the juxtaglomerular apparatus (Latta, 1973) (Fig. 1).
Many investigators using micropuncture and microdissection techniques have shown that renal
renin is released from the cells of the afferent arteriole, and that demonstrable renin activity is absent
from other cells of the juxtaglomerular apparatus
(Faarup, 1968; Faarup, 1971; Cook, 1971). Furthermore, immunological techniques in conjunction
with flourescence microscopy have yielded a similar
pattern of renin in the nephron (Warren et al., 1966;
Hartroft et al., 1964). Renin is secreted directly into
the afferent arteriolar lumen (Horky et al., 1971,
1973). A renal micropuncture study has shown that
the concentration of renin in the efferent arteriole
is lower than in the aorta (Morgan and Davis, 1975).
This observation suggests that renin also may be
released into the interstitium and may enter the
circulation at the capillary level. The concept that
renin is released into the interstitium is supported
to some extent by the finding that the renin concentration in renal lymph is approximately 10-fold
higher than in renal venous blood (Lever and Peart,
1962; Hoise et al., 1970; Horky et al., 1971; Horky et
al., 1973), but this interpretation may be misleading
because of differences in flow of lymph vs. arteriolar
plasma. Theoretically, secretion of renin into the
interstitium would allow enough time for renin substrate to be converted into angiotensin I and, subsequently, to angiotensin II. This mode of renin
secretion would be consistent with a local action of
the renin-angiotensin system within the kidney. If
renin were released directly into the afferent arteriole, angiotensin formation might not occur rapidly
enough to provide an intrarenal site of angiotensin
action.
Interestingly, the renal tissue content of renin
decreases from the superficial to the deep layers of
the cortex, and it has been shown recently that
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CIRCULATION RESEARCH
VOL. 48, No. 2, FEBRUARY 1981
Sympathetic
Neuron
Afferent
Arteriole
Juxtaglomerular
Cells
Distal
Tubule
FIGURE 1 Diagramatic
representa-
tion of the renal juxtaglomerular apparatus showing the afferent and efferent arterioles, juxtaglomerular
cells, and macula densa.
Glomerulus
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renin release is higher in the superficial than in the
deep cortical and medullary nephrons (Peart, 1959;
Brown et al., 1966; Jones et al., 1979). This evidence
suggests that angiotensin II may not be formed
homogeneously throughout the kidney.
Localization of Converting Enzyme Activity
within the Kidney
Angiotensin I does not have significant activity
within the kidney, and converting enzyme is necessary to produce a biologically active peptide
(DiSalvo et al., 1971). Available evidence suggests
that converting enzyme activity is present in the
kidney, so that intrarenal formation of angiotensin
II can occur (Granger et al., 1972). Caldwell et al.
(1976) labeled an antibody specific for rabbit pulmonary angiotensin-converting enzyme with fluorescein. In the kidney, staining was localized to the
endothelial cells of renal arterioles and to glomerular and interglomerular capillaries. In these experiments, converting enzyme also was found on epithelial cells of the proximal tubule. Further studies
by Ward et al. (1975) demonstrated that the enzyme
was located in very high concentrations on the
brush borders of these cells.
The presence of converting enzyme activity in
the kidney also has been inferred indirectly from
the reduction in renal blood flow produced by intrarenal infusion of angiotensin I. Assuming that the
reduction in renal blood flow is due solely to the
conversion of angiotensin I to II, several investigators have reported 7-19% conversion across the
kidney (Franklin et al., 1970; Regoli and Cauthier,
1971).
Formation of Angiotensin II within the
Kidney
It has been suggested that converting enzyme
activity also is present in renal lymph. The concen-
tration of angiotensin II in renal lymph is far higher
than in renal venous blood, suggesting that angiotensin II may be formed within the interstitial compartment (Baile et al., 1971). This may explain the
low rates of conversion of angiotensin I to II across
the vascular space of the kidney. In addition, angiotensin II immunoreactive material, strongly resembling angiotensin II in many of its physiocochemical
properties, is present in 10- to 20-fold higher concentrations in renal tissues than in aortic blood
(Mendelsohn, 1976; Mendelsohn, 1979). This material is not related to contamination by plasma
angiotensin II, since the tissue concentration of
angiotensin II exceeds that which can be accounted
for by trapped blood (Mendelsohn, 1979) and is
unaltered by perfusion of the renal vasculature
(Mendelsohn, 1979). This evidence strongly suggests that angiotensin II is formed locally within
the kidney. Since converting enzyme activity is
present in the interstitial and intravascular spaces
along with renin substrate (Horkey et al., 1971;
Horky et al., 1973), the generation of angiotensin II
from blood borne and/or intercellularly generated
angiotensin I should occur. As discussed above,
renin probably is released into the lumen of the
afferent arteriole as well as into the interstitial
space (Horkey et al., 1971; Horky, 1973; Morgan
and Davis, 1975). Angiotensin I could be generated
in the afferent arteriole and pass into the glomerulus, either as angiotensin I or II, since converting
enzyme activity is located on the endothelial surfaces of these vessels (Caldwell et al., 1976). The
locally generated octapeptide then could exert its
effects on the afferent arteriole and in the glomerulus. Osborne et al. (1975) have demonstrated by
autoradiography that 3H-angiotensin II administered into the rat aorta in vivo localizes in the
mesangial cells of the glomerulus. Also, Sraer et al.
(1974) have produced evidence for specific binding
INTRARENAL RENIN-ANGIOTENSIN SYSTEM/Leuens et al.
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sites for !25I-angiotensin II in isolated rat glomeruli.
These observations are consistent with a possible
glomerular site of action of angiotensin II. Angiotensin II also may pass through the glomerulus,
interact with the efferent arteriole, and pass into
the peritubular capillaries where it might influence
renal tubular function. Alternatively, angiotensin II
could leak into the efferent arteriole from the interstitial space (Morgan and Davis, 1975). The molecular weights of angiotensins I and II allow their
filtration through the glomerular membrane and
into the proximal tubule. The presence of converting enzyme activity on the brush border of the
proximal tubular cells could catalyze the conversion
of filtered angiotensin I to the octapeptide. Angiotensin II has been shown to bind to the brush
borders of these cells and to induce a change in the
ability of these cells to transport sodium (Steven,
1974; Harris and Young, 1977; Freedlender et al.,
1977; Freedlender et al., 1979; Freedlender et al.,
1980).
Theoretically, these anatomic-physiological relationships could allow intrarenally generated angiotensin II to alter renal function. However, since
the half-life of plasma renin is 10-15 minutes, the
kidney is exposed continuously to blood-borne angiotensins I and II generated extrarenally. The interrelationship and coordination of renal function
between these routes of angiotensin generation are
unknown at the present time.
Studies of the Functional Role of the
Intrarenal Renin-Angiotensin System
Effects of Exogenous Angiotensin II on Renal
Function
As discussed above, all of the components of the
renin-angiotensin system are present within the
kidney in close association with the component
structures of the juxtaglomerular apparatus, and
intrarenal formation of angiotensin II does occur
(Granger et al., 1972; Thurau and Mason, 1974;
Caldwell et al., 1976). It is possible, therefore, that
at least a portion of the renal sodium and water
retention accompanying activation of the renin-angiotensin system might be due to a direct action of
intrarenally produced angiotensin II on renal function as postulated by several investigators
(Schmidt, 1962; Thurau, 1963; Guyton et al., 1964;
Thurau, 1974; Caldwell et al., 1976; Davis, 1977;
Hall et al., 1977a; Ploth and Navar, 1979). In support
of the contention that angiotensin II can affect
renal function, experiments have shown that intrarenal infusions of low subpressor doses of the hormone which do not alter peripheral circulating angiotensin II levels (Blair-West et al., 1971) consistently result in decreased renal blood flow and glomerular filtration rate (Bock et al., 1968; Navar and
Langford, 1974). The reduction in renal blood flow
following angiotensin infusion is greater than the
159
fall in glomerular filtration rate, leading to an increased filtration fraction (Navar and Langford,
1974). This observation suggests that angiotensin II
preferentially may constrict the efferent postglomerular arterioles. As a consequence of the reduction
in glomerular filtration rate, there is a concurrent
decrease in the excretion of water and electrolytes
(Barraclough et al., 1967; Malvin and Vander, 1967;
Johnson and Malvin, 1977). This may be a direct
consequence of lower renal blood flow, lower distal
tubular delivery of sodium, or an effect of angiotensin II to increase sodium and water uptake across
the renal tubules (Navar and Langford, 1974).
In producing these changes in renal function,
exogenously administered angiotensin II may act
on all of the blood vessels and renal tubules in
intimate contact with the renal blood supply. However, intrarenally produced angiotensin may not be
formed in equal amounts throughout the kidney,
and therefore, may not interact with all of the
vessels and/or tubules stimulated by the exogenous
peptide. Therefore, the renal effects of exogenous
angiotensin may bear little or no relationship to
those of the intrarenally formed peptide.
Effects of Intrarenal Administration of
Blockers of the Renin-Angiotensin System on
Renal Function
To counter this objection, the role of the intrarenal renin-angiotensin system has been investigated by inhibition of the formation of endogenous
angiotensin II with converting enzyme inhibitors
(teprotide and captopril) or by using peptide antagonists that inhibit the interaction of angiotensin
with its tissue receptors. Clearly, inhibition of the
expression of intrarenally formed angiotensin II
should lead to profound changes in renal function
if the endogenous peptide has important effects in
the kidney. Early studies of renal arterial infusion
of the angiotensin II receptor antagonist, saralasin,
into animals after activation of the endogenous
renin-angiotensin system by sodium depletion,
renal artery occlusion, vena caval constriction or
high output heart failure have demonstrated decreased renal vascular resistance with consequent
large increases in renal blood flow (Freeman et al.,
1975a; Mimran et al., 1974; Satoh and Zimmerman,
1975). In most of these studies, no changes in glomerular filtration rate or electrolyte and water excretion were observed. These findings suggested
that the intrarenal renin-angiotensin system plays
an important role in regulating renal hemodynamics, but does not contribute to the regulation of
water and electrolyte balance. In many of these
early studies, the changes in renal function were
associated with a reduction in mean arterial pressure. Although the increased renal blood flow in
response to intrarenal inhibition of the renin-angiotensin system could not be due to the fall in blood
pressure, reduced renal perfusion pressure could
160
CIRCULATION RESEARCH
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have masked any changes in the excretion of sodium
and water. Furthermore, other physiological systems may have been activated to control water and
electrolyte excretion under the pathological conditions of caval constriction, high output heart failure,
and renal artery stenosis, which may have obscured
changes in renal function following inhibition of the
renin-angiotensin system.
More recently, the role of the intrarenal reninangiotensin system in the control of renal function
has been investigated in anesthetized and conscious
dogs (Hall et al., 1977b; Trippodo et al., 1977).
These studies were performed after physiological
activation of the renin-angiotensin system with dietary sodium restriction or water deprivation. In
these experiments, intrarenal infusion of angiotensin receptor antagonists at doses that only slightly
reduced arterial pressure resulted in increased renal
blood flow, glomerular filtration rate, and sodium
and water excretion. These data suggested that the
intrarenal renin-angiotensin system could exert an
action on renal sodium and water handling, as well
as renal hemodynamics.
Since many angiotensin receptor antagonists are
partial agonists and any such action would modulate the induced responses ascribed to receptor
blockade, studies using the angiotensin-converting
enzyme inhibitor, teprotide, were performed. Kimbrough et al. (1977) separately infused both saralasin and teprotide into the renal artery of sodiumdepleted conscious dogs at doses that did not
change mean arterial pressure. Both compounds
gave quantitative increases in glomerular filtration
rate, renal blood flow, and sodium excretion, providing further evidence that the endogenous intrarenal renin-angiotensin system has the capability of
influencing renal function. Changes in glomerular
filtration rate, renal blood flow, and sodium excretion were not present in sodium-replete animals,
indicating that activation of the renin-angiotensin
system is an essential condition for the control of
renal function by intrarenal angiotensin II. Kimbrough (1977) further demonstrated increased renal
free water formation in reponse to intrarenal infusion of saralasin and teprotide, independent of
changes in GFR and sodium balance. Precise interpretation of these observations was difficult, however, because the animals were studied in an uncontrolled state of water balance.
Primary Antidiuretic Action of Intrarenal
Angiotensin II.
The effects of blockade of intrarenal angiotensin
II formation with teprotide now have been studied
under rigidly controlled conditions of hydropenia or
water diuresis (Levens et al., in press, a). After
activation of the renin-angiotensin system by sodium depletion, intrarenal infusion of teprotide elicited consistent decreases in urinary osmolality and
consistant increases in renal blood flow, glomerular
VOL. 48, No. 2, FEBRUARY
1981
filtration rate, urine volume, and free water formation. In these experiments, renal blood flow consistently increased to a greater degree than glomerular
filtration rate, resulting in a decreased filtration
fraction in response to angiotensin inhibition by
teprotide. This observation supports the concept
that angiotensin II preferentially constricts efferent
arterioles. Glomerular filtration rate and circulating
vasopressin are determinants of renal free water
excretion (Wesson, 1969; Deetjen, 1975). However,
changes in angiotensin-dependent renal free water
formation were dissociated from changes in glomerular filtration rate and circulating vasopressin. Further, intrarenal teprotide increased urine volume
and free water formation under conditions of dehydration and administration of exogenous vasporessin to produce physiologically maximal circulating vasopressin. Under these circumstances, high
baseline circulating vasopressin should have obscured any changes in endogenous vasopressin
release which might have occurred from the pituitary. Therefore, the observed changes in renal free
water formation almost certainly are due to a primary direct intrarenal antidiuretic action of angiotensin II. These results are consistent with investigations showing that intrarenal angiotensin II
blockade delays recovery of urine osmolality after
administration of furosemide (Imbs et al., 1978).
Studies from our laboratory using intrarenal infusion of saralasin have substantiated these results,
thereby supporting the concept that inhibition of
angiotensin II rather than potentiation of kinins is
the primary cause of the observed results (Levens
et al., 1979a). Recent studies, demonstrating that
low dose intravenous angiotensin II infusion reversed the effect of chronic captopril treatment on
blood pressure and sodium excretion, have confirmed this impression (McCaa, 1979).
Effects of Intrarenal Angiotensin II on
Sodium Transport
Formation of a concentrated urine is brought
about by the active transport of chloride and sodium out of the ascending limb of the loop of Henle
to produce a hyperosmotic environment with respect to the fluid in the collecting ducts. On the
basis of our findings, we advanced the hypothesis
that angiotensin II stimulates sodium transport in
the ascending limb of the loop of Henle. Inhibition
of intrarenal angiotensin II formation with teprotide could decrease the medullary osmotic gradient
and increase free water formation.
Some evidence exists in favor of the hypothesis
that angiotensin II acts on sodium transport in this
part of the kidney. Munday et al. (1971) used renal
cortical slices and demonstrated that angiotensinstimulated salt and water transport is mediated by
a ouabain-insensitive, potassium-independent sodium pump. This sodium pump is similar to that
described by Wittembury and Proverbio (1970) in
INTRARENAL RENIN-ANGIOTENSIN SYSTEM/Levens et al.
guinea pig renal cortical slices, which is inhibited
specifically by ethacrynic acid, a diuretic that acts
predominately on the active reabsorption of sodium
and chloride from the ascending limb.
Angiotensin-induced changes in renal blood flow
could account for the water and electrolyte changes
in response to intrarenal angiotensin blockade.
However this is unlikely, as Ploth and Navar (1979),
studying tubular sodium trasnsport by micropuncture following intrarenal inhibition of the reninangiotensin system in dogs, demonstrated that teprotide and saralasin depress tubular transport between the proximal and early distal tubule.
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Reappraisal of the Intrarenal ReninAngiotensin System with Doses of Blockers
which do not Influence the Systemic ReninAngiotensin System.
In all of the previous studies of intrarenal angiotensin inhibition, changes in renal function as a
consequence of infusion of angiotensin inhibitors
into the kidney have been interpreted primarily as
due to blockade of the intrarenal renin-angiotensin
system. Clearly, the infused blockers could be leaking outside the kidney, stimulating or inhibiting
production of other factors known to alter renal
function. Under conditions of sodium depletion,
intravenous infusion of teprotide or saralasin results
in large reductions in mean arterial pressure. In
many of the previously reported infusion studies,
intrarenal infusion of the angiotensin inhibitors produced little if any change in arterial pressure. This
has been taken as evidence that the blockers did
not leave the kidney. However, intrarenal infusion
of saralasin or teprotide produces rapid elevation of
plasma renin activity and, hence, in systemic
plasma angiotensin I and II concentrations (Bing
and Poulsen, 1975). Secretion of renin is achieved
by removal of the negative feedback of angiotensin
II on renin release. If intrarenal infusion of the
inhibitors results in exclusive renal blockade, then
one might expect an elevation of arterial blood
pressure in the absence of peripheral blockade. In
all of the previous experiments, arterial pressure
remained the same or even decreased.
Based on the hypothesis that the angiotensin
blockers might be leaving the kidney and inhibiting
the peripheral as well as intrarenal renin-angiotensin systems, we induced systemic pressor responses
with intravenous bolus injections of 3.2 jug of angiotensin I during simultaneous intrarenal infusions of
differing doses of saralasin (Levens et al., 1979a).
We demonstrated that saralasin at doses higher
than 0.07 itg/kg per min leaked from the kidney
into the systemic circulation and attenuated angiotensin I-induced responses. In all of the studies
reported previously, doses of 0.20-2.5 jug/kg per min
have been used, suggesting that inhibition of the
systemic renin-angiotensin system might have accounted for the observed changes in renal function.
161
We further demonstrated that the maximum dose
allowable for specific renal blockade inhibited renal
angiotensin II receptors, as it totally blocked the
reduction in urine flow produced by the simultaneous intravenous infusion of 0.1 jig/min of angiotensin II. Intrarenal infusion of this low dose of
saralasin reproducibly increased renal blood flow,
glomerular filtration rate, and sodium, potassium
and water excretion.
These experiments demonstrated that the intrarenal renin-angiotensin system exerts physiological
effects on a variety of important renal functions and
that caution should be exercised in the interpretation of studies in which inhibitors at doses greater
than 0.07 /xg/kg per min are infused into the kidney
and assumed to block only the intrarenal reninangiotensin system. Since angiotensin II may be
formed in the renal interstitial compartment, the
availability of the inhibitors to this compartment
should be determined to facilitate interpretation of
these studies.
Studies of the Intrarenal Vascular
Effects of Angiotensin
Effects of Angiotensin II on the Function of
the Afferent and Efferent Arterioles.
The previous discussion focused on the observations that intrarenal infusion of angiotensin antagonists or converting enzyme inhibitors increases
renal blood flow proportionately more than glomerular filtration rate with a consequent decrease in
filtration fraction. This suggests that intrarenally
formed angiotensin may control renal hemodynamics by preferential vasoconstriction of efferent arterioles. In support of this hypothesis, Krahe et al.
(1970) and Davalos et al. (1978) demonstrtated that
infusion of angiotensin II or renin substrate into the
isolated perfused kidney reduces renal pulsatile flow
but increases glomerular filtration rate and filtration fraction. Furthermore, the effects of renin substrate could be inhibited completely by depleting
the kidneys of renin or adding teprotide or saralasin
to the perfusion fluid, providing further evidence
that intrarenally generated angiotensin II interacts
at the level of the efferent arteriole. However, it is
entirely possible in these experiments that angiotensin formation induces a selective redistribution
of blood flow toward corticomedullary nephrons,
which possess a higher filtration fraction than outer
cortical nephrons.
In accord with this hypothesis are observations
showing that angiotensin II decreases blood flow to
the outer renal cortex (LaGrange and Schmidt,
1975). However, the octapeptide exerts a variable
effect on inner cortical flow, which appears to be
related to the induction of renal prostaglandin synthesis. When prostaglandin synthesis is inhibited
with indomethacin (Itskovitz and McGiff, 1974),
angiotensin also decreases inner cortical and med-
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ullary blood flow. Interestingly, infusion of angiotensin I into the isolated perfused kidney in the
presence or absence of a converting enzyme inhibitor induces a selective decrease in the inner cortical
and medullary fractions of renal blood flow without
affecting outer cortical flow. Although it is possible
that angiotensin I may determine the partitioning
of blood flow intrarenally (Itskovitz and McGiff,
1974; Vane and McGiff, 1975), the kidney contains
large quantities of enzymes capable of converting
angiotensin I to II. As none of these studies with
angiotensin I included measurement of angiotensin
II in the renal venous effluent, a direct action of
intrarenally produced angiotensin I has not been
established.
Although most of the evidence suggests that the
intrarenal renin-angiotensin system controls renal
hemodynamics predominantly through an action
on postglomerular vessels, there is some conflicting
evidence. For example, Ploth and Navar have
shown with micropuncture and clearance techniques in anesthetized dogs that intrarenal infusion
of teprotide increases renal blood flow (Ploth and
Navar, 1979; Navar et al., 1979). However, in these
experiments, whole kidney and single nephron glomerular filtration rates and estimated glomerular
pressure did not change significantly. Afferent arteriolar resistance decreased significantly, although
there was no change in resistance of the efferent
arteriole. These investigators infused teprotide into
the kidney at a rate of 5 mg/hr. This is in excess of
a dose of 0.2 /i.g/kg per min, which, as we have
shown by measuring plasma converting enzyme
activity in conscious dogs, accumulates outside the
kidney within 10 minutes of initiation of intrarenal
infusion. It should be pointed out that other investigators have obtained evidence for an afferent action of angiotensin (Navar and Langford, 1974).
However, the majority of these studies have used
the infusion of the exogenous peptide, which may
not mimic the actions of the endogenous hormone.
Therefore, we believe on the basis of available
evidence that intrarenally produced angiotensin II
preferentially constricts the efferent arteriole.
Effects of Angiotensin II on the Glomerular
Capillaries
In addition to acting on glomerular arterioles,
angiotensin II also appears to have an action on
glomerular capillaries. Intravenous infusion of subpressor doses of angiotensin II results in a reduction
of the glomerular permeability coefficient (Blantz
et al., 1976). It is not known if this is a direct effect
on the capillary cells or indirectly due to contraction
of the mesangium. The mesangial cells supporting
the capillary loops do contain contractile fibers.
Furthermore, the major part of low doses of 12SIangiotensin II injected into the renal artery of the
rat localizes in the mesangium (Osborne et al.,
1975). Other investigators have shown that mesan-
VOL. 48, No. 2, FEBRUARY
1981
gial cells grown in culture contract in response to
angiotensin (Ausiello et al., 1979).
Mesangial cells link the glomerulus to the juxtaglomerular apparatus and also produce cytoplasmic
processes that project into the lumen of the glomerular capillaries. It is, therefore, intriguing to
speculate that the mesnangium may contract in
response to both intrarenally and systemically
formed angiotensin II. Contraction of the glomerular capillaries would reduce glomerular capillary
hydraulic conductivity, and hence effective filtration pressure, leading to a decreased filtration fraction. Thus, intrarenally formed angiotensin may
contribute to renal hemodynamics by an action on
the efferent arteriole and the mesangial cells.
Intrarenal Role of Angiotensin III
Although it generally is accepted that angiotensin II is the main effector of the renin-angiotensin
system, there is now considerable experimental evidence to suggest that other angiotensin peptides
exhibit considerable activity in a number of sensitive tissues. Most studies in the kidney have concentrated on the effect of angiotensin II. Recently,
however, Freeman et al. (1975) infused both angiotensins II and III ([des-Asp']-angiotensin II) into
the renal artery of sodium-replete dogs and noted
comparable reductions in renal blood flow and renin
release in response to both compounds. In contrast,
Taub et al. (1977) showed angiotensin II to have a
greater effect on the renal vasculature than angiotensin III. Furthermore, in Taub's studies, crosstachyphylaxis between the peptides occurred,
which led to the assumption that angiotensins II
and III act in the kidney on a single receptor which
has structural properties that differ from those of
the systemic vascular angiotensin receptor. Taub et
al. noted that the heptapeptide antagonist, [desAsp'Jle^-angiotensin II, induced a greater increase
in renal blood flow than saralasin after activation
of the renin-angiotensin system by caval occlusion.
This may suggest that angiotensin II is a primary
agonist on the renal vasculature. Hall et al. (1979)
have investigated the role of intrarenally produced
angiotensin III by infusing the heptapeptide antagonist [des-Asp',Ile8]-angiotensin II intrarenally in
sodium-depleted dogs. Intrarenal infusion of the
inhibitor did not alter any aspect of renal function.
However, Freeman et al. (1975b) have shown that
intrarenal infusion of angiotensin III results in a
large decrease in plasma renin activity, suggesting
that the heptapeptide, like angiotensin II, inhibits
renal renin release. Hence, the renal effects of inhibition of angiotensin III may be masked by a
concomitant increase in circulating systemic angiotensin II. Furthermore, Hall et al. (1979) failed to
determine if the heptapeptide antagonist was leaking from the kidney to cause systemic accumulation.
An effect of the inhibition of peripheral angiotensin
III action may have masked any actions due to
INTRARENAL RENIN-ANGIOTENSIN SYSTEM/Leuens et al.
inhibition of the intrarenal heptapeptide.
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Evidence for a Direct Tubular Action of
Angiotensin
Experiments involving intrarenal infusion of angiotensin inhibitors indicate that the intrarenal reninangiotensin system can determine renal hemodynamics and electrolyte and water excretion. However, in these studies, only the net handling of
sodium and water by the entire kidney can be
measured. The inherent nature of these preparations does not allow for separation between (1) a
direct action of the inhibitor to increase electrolyte
excretion by inhibition of an angiotensin-stimulated
tubular transport process, or (2) an indirect effect
on glomerular filtration due to inhibition of angiotensin-induced vasoconstriction. An important
component of the increased sodium and water excretion occurring during the infusion of the antagonists may be the concurrent increase in glomerular
filtration rate and, hence, the filtered sodium load.
However, recent evidence would suggest that part
of the increased renal sodium excretion observed in
these experiments may be due to inhibition of a
direct action of angiotensin on renal tubular transport of sodium and water.
In Vivo Studies
Early studies on the kidney in vivo indirectly
suggest a direct tubular effect of angiotensin II. For
example, intravenous infusion of angiotensin II in
dogs elevates the distal tubular concentrations of
sodium, indicating that the peptide inhibits distal
tubular sodium transport (Vander, 1963). An inhibitory action of the hormone on proximal as well as
distal sodium transfer has been inferred from the
delayed collapsed of the tubular lumen following
angiotensin infusion after renal artery constriction
(Leyssac, 1967). However, these studies have not
been confirmed by other investigators (Nagel et al.,
1966).
Micropuncture Studies
More recently, studies on the in situ kidney show
that angiotensin exerts a dose-dependent dual action on sodium reabsorption across the renal tubules. A sodium diuresis occurs in rats after administration of high doses of angiotensin, whereas low
infusion rates result in sodium retention (Harris
and Young, 1977). Barraclough et al. (1967) suggested that the effects of angiotensin were due to a
direct action on a tubular transport process. Bonjour and Malvin (1969) concluded that the diuresis
produced by high doses of angiotensin was due to
inhibition of a tubular transport process, whereas
the antidiuretic response to low doses of angiotensin
was regarded as secondary to renal vasoconstriction
and a reduced glomerular nitration rate. Micropuncture and microperfusion studies of single nephrons also have emphasized the variability of tubular
163
sodium transport following intravenous administration of angiotensin. A major problem in these in
vivo studies is the difficulty in separating the hemodynamic effects from the direct tubular effects
of the hormone. Furthermore, systemic administration of angiotensin could result in diversion of cortical blood to the medulla and indirectly influence
the tubular handling of sodium and water in the
cortical nephrons studied in the micropuncture and
microperfusion experiments. Published observations indicate variable changes in inner cortical and
medullary blood flow in response to exogenous angiotensin II (LaGrange and Schmidt, 1975; Itskovitz
and McGiff, 1974; Vane and McGiff, 1975). However, the situation may be markedly different for
angiotensin formed intrarenally, as the major fraction of the renin is released from the cells in the
outer cortical nephrons (Peart, 1959; Brown et al.,
1966; Jones et al., 1979).
A recent development has been the use of freeflow micropuncture combined with perfusion of the
peritubular capillaries with angiotensin. Steven
(1974) used this technique and found that angiotensin II inhibited proximal sodium transport, whereas
Harris and Young (1977) demonstrated that the
octapaptide exerted a dose-dependent dual action
on sodium transport (low doses stimulated whereas
high doses inhibited absorption). Thus, variation in
the response of the kidney to angiotensin may be
due to differences in the relative doses of the hormone used in these experiments.
Although the aforementioned in vivo and micropuncture experiments are suggestive of a direct
effect of angiotensin on sodium transport by the
renal tubule, the evidence is speculative, as infused
angiotensin may change the vascular permeability
of the glomerular or peritubular capillaries leading
to changes in interstitial fluid pressure and indirectly affect the renal handling of sodium and water.
For this reason, the effect of angiotensin on renal
slices and isolated tubules has been studied. This
approach excludes any indirect action of angiotensin through release of other hormones such as vasopressin and aldosterone which can affect renal
function.
Studies of Renal Slices and Isolated Tubule
Preparations
Angiotensin II in low doses increases the rate of
active sodium extrusion by rat renal cortical slices.
This effect does not involve cyclic AMP and is
blocked by inhibitors of the translation level of
protein synthesis (Munday et al., 1972). Recently,
Freedlender and Goodfriend (1977) have shown
that angiotensin II can bind to and influence sodium
transport in isolated proximal renal tubules. In
these studies, the tubules are sodium-loaded and
then incubated with the octapaptide. Low doses of
angiotensin II (1(T12 to 10~9 M) are associated with
increased sodium extrusion from the cells, suggest-
164
CIRCULATION RESEARCH
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ing that antiotensin II is directly stimulating sodium
pump activity. In contrast, high doses of angiotensin
II (1CT9 to 10~fi M) were linked to decreased sodium
extrusion, suggesting that at these doses the hormone was able to inhibit sodium pump activity. In
a series of separate experiments, these authors demonstrated binding of biologically active 12:'I-labeled
angiotensin in the tubules. Scatchard analysis of
the binding showed a high affinity site at doses that
produced increased sodium extrusion and a low
affinity site at doses that inhibited transport
(Freedlender and Goodfriend, 1977). Furthermore,
autoradiographic studies by Freedlender et al.
(1980) indicate that the high affinity angiotensin
binding site is on the basolateral membrane of the
tubular cell, whereas the low affinity site is associated with the brush border membrane. These observations have important physiological implications and suggest that blood-borne angiotensin II
interacts with high affinity receptors on the basolateral membrane of the cell to mediate sodium
absorption. The purpose and function of the low
affinity sites mediating sodium extrusion and located on the brush border membrane are open to
speculation.
Studies of Non-Renal Transporting Epithelia
Because of the nonphysiological nature of isolated tubules and renal cortical slices, several investigators have sought to determine the action of
angiotensin on other transporting epithelia. Tissue
such as frog skin and the mammalian intestine have
structural and functional properties similar to those
of the mammalian nephron (Dicker, 1970) and respond to angiotensin with uptake of sodium and
water at low doses and inhibition of transport at
high doses (Coviello, 1972; Bolton et al., 1975).
Recently we (Levens et al., 1979b, 1980) have shown
that the stimulation of intestinal sodium transport
measured as water transport produced by angiotensin can be inhibited by treatment of the animals
with phentolamine or reserpine. This suggests that
in the intestine the stimulation of transport by low
doses of angiotensin is mediated via release of norepinephrine from the sympathetic nerve endings in
close proximity to the transporting epithelial cells.
We have demonstrated that inhibitors of angiotensin, although potent antagonists of the parent
peptide in vascular tissue, are equipotent to or have
even greater activity than the parent peptide in
stimulating sodium and water uptake across the
intestine in vivo (Levens et al., in press, b). Further,
Freedlender and Goodfriend (1977) have shown
that 8-substituted analogs of angiotensin are potent
full agonists of sodium transport by proximal tubular cells. In view of these observations, care
should be exercised in the interpretation of data
from experiments in which these analogs have been
infused intrarenally. Clearly, they could inhibit the
vascular effects of angiotensin, but act synergistically to stimulate tubular transport.
VOL. 48, No. 2, FEBRUARY
1981
Role of Intrarenal Angiotensin in Renal
Autoregulation
The unique anatomical structure of the juxtaglomerular apparatus and its intimate relationship to
components of the renin-angiotensin system led
Thurau to propose that intrarenally generated angiotensin II may participate in renal autoregulation.
In essence, Thurau hypothesized that changes in
the composition of the distal tubular fluid caused
by increased renal perfusion pressure were sensed
by the specialized cells of the macula densa, leading
to renin release from adjacent juxtaglomerular cells
(Thurau, 1964; Thurau et al., 1967). Angiotensin II
then is generated locally, leading to arteriolar vasoconstriction and a reduction in renal perfusion
pressure.
Studies Supporting the Role of Angiotensin
II in Renal Autoregulation
In support of this hypothesis, there is now a
considerable amount of evidence to suggest that
increased distal sodium and chloride transport in
the macula densa results in renin release from juxtaglomerular cells (Shade et al., 1972; Tuck et al.,
1974; Davis and Freeman, 1976). However, the relationship of these observations to autoregulatory
behavior as a result of changes in the intrarenal
renin-angiotensin system is controversial. Thurau
(1974), Brech et al., (1973) and Kaloyanides et al.
(1977) all have reported that experimental manipulations resulting in decreased renin production by
the kidney produce a loss of autoregulatory ability
in isolated perfused dog kidneys. Intravenous administration of the converting enzyme inhibitor,
teprotide, or of angiotensin analogs have been demonstrated to reduce the feedback response to elevated loop flow rate in the rat kidney (Stowe and
Schnermann, 1974; Stowe et al., 1979). In two-kidney, one-clip Goldblatt hypertensive rats, the contralateral undipped kidney fails to autoregulate,
possibly secondary to marked renin depletion in the
non-autoregulated kidney (Ploth et al., 1977).
Taken together, these observations suggest that
intrarenally generated angiotensin may alter renal
autoregulatory behavior.
Studies Failing to Support the Role of
Angiotensin II in Renal Autoregulation
Hall et al. (1977a, 1977c) demonstrated that
blockade of the renin-angiotensin system following
renin depletion or intrarenal infusion of an angiotensin II receptor antagonist results in attenuation
of glomerular filtration rate but not of autoregulation of renal blood flow. These investigators, therefore, hypothesized that the resistance of both afferent and efferent arterioles diminishes as a result of
decreased arterial pressure in the absence of the
renin-angiotensin system. However, in the presence
of an intact renin-angiotensin system, autoregulatory renal vasodilation results in large increases in
INTRARENAL RENIN-ANGIOTENSIN SYSTEM/Leuens et al.
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renin release and angiotensin II production with
consequent increased filtration by constriction of
the efferent arteriole. Clearly, renin depletion also
will affect angiotensin production systemically,
whereas the inhibitor, which was infused at a dose
of 0.25 ^tg/kg per min, leaks from the kidney and
attenuates the activity of the systemic renin-angiotensin system.
Interestingly, many investigators have failed to
alter autoregulatory ability with intrarenal infusions of angiotensin antagonists during alterations
in renal perfusion pressure (Anderson et al., 1975;
Gagnon et al., 1974; Schmidt et al., 1973). However,
as plasma renin activity increases in response to
intrarenal infusion of antagonists, it is possible that
increased systemic angiotensin II production could
mask any changes in renal autoregulatory behavior
produced by inhibition of intrarenal angiotensin. In
any experiments dealing with the problem of autoregulation, it is important to determine not only
whether the infused blockers are leaving the kidney,
but also the extent of intrarenal receptor blockade.
It is immediately obvious from the literature that
the role of the intrarenal renin-angiotensin system
in the autoregulation of renal hemodynamics is
controversial. No studies to date involving micropuncture or whole animals have separated adequately inhibition of the function of the intrarenal
from the peripheral renin-angiotensin system.
The Intrarenal Renin-Angiotensin
System: Speculations on Its Role in Fluid
and Electrolyte Homeostasis
A considerable amount of evidence now suggests
that angiotensin II generated locally within the
kidney can influence renal function under conditions of sodium and water restriction. On the basis
of this evidence, we would like to speculate on a
hypothetical sequence of events involving the reninangiotensin system that leads to the profound
changes in renal function following sodium restriction. After a small reduction in the distal sodium
load to the macula densa, renin is released into both
the afferent arteriole and the intercelluar compartment. As the renal tubules have a lower threshold
for angiotensin than the renal vasculature, tubular
transport is stimulated. If this fails to correct the
decreased distal sodium load, more renin is released
until the vascular threshold is reached. At this
point, constriction of the efferent arteriole and glomerular mesangium results in diversion of blood
flow to the inner cortex and medulla. This leads to
decreased renal blood flow and glomerular filtration
rate and further conservation of fluid volume.
Increasing sodium deprivation will produce
greater renin release, causing the enzyme to escape
the kidney and enter the systemic circulation. As a
result of the peripheral generation of angiotensin II,
aldosterone is secreted from the adrenal cortex and
stimulates sodium uptake from the distal tubule.
Further elevation of systemic angiotensin II con-
165
centration will act to reinforce the intrarenal vasoconstrictor effects of intrarenally generated angiotensin, as well as stimulate the release of ADH from
the pituitary.
In summary, we envisage the intrarenal reninangiotensin system as a mechanism to prevent renal
sodium loss following mild sodium restriction.
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N R Levens, M J Peach and R M Carey
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