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Biological Functions of Angiotensin and Its Receptors: T. Matsusaka and I. Ichikawa
Biological Functions of Angiotensin and Its Receptors: T. Matsusaka and I. Ichikawa
Biological Functions of Angiotensin and Its Receptors: T. Matsusaka and I. Ichikawa
BIOLOGICAL FUNCTIONS OF
ANGIOTENSIN AND ITS RECEPTORS
T. Matsusaka and I. Ichikawa
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Annu. Rev. Physiol. 1997.59:395-412. Downloaded from www.annualreviews.org
KEY WORDS: aldosterone, JG cells, extracellular matrix, heart failure, renal failure
ABSTRACT
Angiotensin receptors are present in a number of organs and systems including
heart, kidney, gonad, and placenta; pituitary and adrenal glands; the peripheral
vessels, and the central nervous system. This octapeptide exerts diverse effects
that include induction of cell hypertrophy and/or hyperplasia and a stimulation
of hormone synthesis and ion transport in the heart, kidney, and adrenal, pri-
marily through type 1 (AT1) receptors. In the kidney, several heterogeneous cell
populations—endothelial, epithelial, and vascular—carry AT1 receptors. Some
studies suggest that AT2 receptors are also functional, but the cell type carrying
this receptor and the nature of its specific function have not been fully eluci-
dated. Although studies indicate that AT1 receptors are affected in response to
physiological and pathophysiological manipulations, the functional significance
of these modulations remains largely uncertain. Nevertheless, recent human ge-
netic studies indicate that polymorphisms in AT1 receptors, as well as in other
angiotensin-related genes, have significant impact on organ remodeling processes
of the heart and the kidney.
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0066-4278/97/0315-0395$08.00
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inter bundle area of the inner zone of the outer medulla (57). An Ang type
1 receptor (AT1) antagonist, losartan, almost completely inhibits the binding
of 125 -I[Sar1 , Ile8 ] Ang II in adult rat kidneys, whereas type 2 receptor (AT2)
antagonist PD123177 has little effect, which indicates that most of the Ang II
receptors in adult kidneys are AT1 receptors, with a limited number of AT2
receptors (81).
Mice and rats, but not humans, have two subtypes of AT1, namely, AT1A and
AT1B. These receptor subtypes are likely the result of gene duplication, which
occurred in rodents prior to the phylogenic divergence between the mouse and
the rat (96). Gasc et al studied AT1A and AT1B expression in rats by in situ
hybridization using specific probes for the 30 noncoding region of their mRNAs
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Figure 1 Regulatory mechanism of renin production and release. AT1 receptor is by far the
most intensely expressed in renin-producing cells. The renin release and production are regulated
primarily by baroreceptor and macula densa mechanisms. The significance of the direct feedback
regulation by Ang II has not been confirmed in vivo. It remains to be determined why renin-
producing cells need to express high-density AT1.
(48). The AT1 receptor antagonist inhibited this gene expression. These find-
ings suggest that Ang II is locally up-regulated in the injured endothelium and
may trigger a cascade involving TGF-β and ECM protein synthesis.
Other studies suggest that Ang II is also involved in interstitial fibrosis. Klahr
and colleagues observed that ACEi and AT1 antagonist significantly blunted
the increase of TGF-β1 and collagen IV mRNAs in experimentally obstructed
rat kidneys, in which a marked interstitial fibrosis would otherwise develop
(45). Johnson et al showed that a chronic infusion of Ang II led to develop-
ment of tubulointerstitial injury with type IV collagen deposition (41). In vitro
studies by Wolf et al demonstrated that Ang II can induce type IV collagen and
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TGF-β in MCT cells, a proximal tubular cell line (94). It was further shown that
Annu. Rev. Physiol. 1997.59:395-412. Downloaded from www.annualreviews.org
interstitial cells express a high level of AT1 receptors (28, 99). In fibroblasts of
cardiac origin, Ang II was shown to induce hypertrophy and hyperplasia along
with the expression of TGF-β1 mRNA (77). Ang II may, therefore, stimulate
the synthesis of ECM proteins in the renal interstitium directly, or via induction
of growth factors.
Ang II may also modulate degradation of ECM. The importance of degrada-
tion mechanisms in the advancement of glomerulosclerosis is supported by the
experimental demonstration that attenuation of ECM accumulation could lead
to a reversal of established glomerulosclerosis (35). ECM proteins are degraded
by a number of proteinases, among which matrix metalloproteinases (MMPs)
play major roles. MMPs are secreted in inactive form, and plasmin is required
for their conversion to active enzymes. Plasmin is generated from plasminogen
by the action of plasminogen activators (PAs), which are also activated by plas-
min, thereby forming a positive feedback loop. This system, which also plays
a central role in fibrinolysis, is tightly regulated by PA inhibitors (PAIs). The
importance of PAI-1 in ECM degradation in the kidney was shown by a study
in which administration of PAI-1-neutralizing antibodies to cultured mesan-
gial cells resulted in a several-fold increase in ECM degradation (6). It has
been shown that Ang II increases PAI-1 mRNA in cultured vascular smooth
muscle cells and vascular endothelial cells (26). In vivo infusion of Ang II
in humans resulted in increased circulating levels of PAI-1 (75). Moreover,
ACEi administration lowers plasma PAI-1 levels in humans (95). Thus Ang II
has a capacity to attenuate fibrinolytic activity and ECM degradation via the
PAI-1-PA-plasmin cascade. Overall, Ang II has the potential to attenuate ECM
degradation via induction of PAI-1.
isolated from the fetus but not on cells derived from the adult (72). The pos-
sibility thus exists that Ang II may participate in the proliferation of glomeru-
lar mesangial cells during nephrogenesis. This hypothesis has been proven
in angiotensinogen null-mutant mice, which had a modest delay in glomeru-
lar maturation (64). Because glomerular maturity was comparable between
homozygous-mutant neonates produced by homozygous versus heterozygous
mothers, Ang II in the maternal circulation appears to have little impact on fetal
glomerular maturation. The delay of glomerular maturity was most prominent
at 1 week of age, and there was no difference in maturity at 3 weeks of age,
indicating that Ang II is necessary for full glomerular maturation in the early
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Hypotension
Growth failure
Glomerulus
Delayed maturation
Resistance to glomerular sclerosis
Impaired size autoregulation
Tubulointerstitium
Interstitial fibrosis
Tubular dilatation
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Hypoplastic papilla
Annu. Rev. Physiol. 1997.59:395-412. Downloaded from www.annualreviews.org
diotomy (15, 82). It remains uncertain, however, whether the locally activated
ACE is sufficient to account for the cardiovascular lesion.
Stimulatory Effect of Angiotensin on Aldosterone Occurs
Through AT1 Receptors and Involves Activation
of Synthesis and Cell Proliferation
Ang II is the major regulator of aldosterone synthesis, and this function is me-
diated by the AT1 receptor (16). Consistent with this function, AT1 is intensely
expressed in the adrenal gland. Gasc et al showed AT1A and AT1B expression
in the rat adrenal by in situ hybridization (28). Zona glomerulosa cells express
a high level of AT1A and AT1B mRNA, with AT1B mRNA expression being
higher than that of At1a.
Ang II is thought to stimulate the secretion of aldosterone in at least three
ways: (a) induction of enzymes that are required for aldosterone synthesis,
(b) stimulation of the proliferation of adrenocortical cells, (c) induction of AT1
receptors (Figure 2). Cholesterol side chain cleavage (P450scc) and aldosterone
synthase (P450aldo) catalyze the early and late rate-limiting steps, respectively.
ACEi was shown to almost completely attenuate the enzyme activity, mRNA,
and protein of both P450scc and P450aldo, which are increased during dietary
sodium restriction in rats (2, 86). Holland et al, utilizing an adrenocortical cell
line (33), showed that the Ang II response element is present within the initial
425 base pairs (bp) of the mouse P450aldo gene promoter.
In dietary sodium-restricted rats, the number of glomerulosa cells is in-
creased, and enalapril completely inhibits the increase, indicating that Ang
II has a proliferative effect on zona glomerulosa cells in vivo (59). Tian et al
showed that Ang II stimulates thymidine incorporation and proliferation in
cultured bovine glomerulosa cells via the AT1 receptor (84). In rats fed a low-
sodium diet, the major site of cell replication (assessed by BrdU-incorporation)
was not in the zona glomerulosa but in the transitional zone, which is located
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between the zona glomerulosa and zona fasciculata (59). This finding indi-
cated that under sodium-deficient conditions, the major proliferating adrenal
cells are not the glomerulosa cells, which are already differentiated, but stem
cells, which are localized in the transitional zone.
Dietary sodium deficiency is the most common stimulus for increasing aldos-
terone secretion under physiological conditions. As discussed above, blockade
of Ang II markedly attenuates aldosterone secretion, as well as expression of
P450scc and P450aldo, and glomerulosa cell proliferation during sodium re-
striction. Ang II is, therefore, a potent mediator of aldosterone secretion during
sodium depletion, although it is not known whether the increase in aldosterone
is entirely dependent on Ang II. Several early observations discounted this
notion. For example, plasma renin and Ang II levels often dissociate from
aldosterone secretion (9). Nephrectomized rats respond to sodium depletion
with a significant rise in aldosterone secretion (66). However, more recently
these phenomena have been attributed to either one or a combination of the
two mechanisms involving Ang II; that is, activation of the intra-adrenal renin-
angiotensin system (23, 71) and/or alteration of the adrenal sensitivity to Ang
II (1).
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plasma renin activity, it increases adrenal renin (63). Therefore, it has been pro-
posed that locally generated Ang II in the adrenal glomerulosa cells mediates
the aldosterone secretion induced by potassium. Local Ang II is shown to be
necessary not only for potassium-stimulated aldosterone secretion but also for
basal ACTH-stimulated and sodium depletion-induced aldosterone secretion
(29, 66).
bound endogenous Ang II, the Ang II receptor down-regulation was attributed
to a phenomenon other than increased prior occupancy of the receptor by en-
dogenous Ang II (8).
Although it is widely believed that the Ang II receptor in adult rat or hu-
man kidneys is AT1, it remains inconclusive whether the down-regulation of
glomerular Ang II binding sites is entirely reflective of AT1 because there is cur-
rently no perfect receptor subtype-specific ligand available for study. Losartan,
the most widely used synthetic AT1 receptor antagonist, binds to rat glomeruli
and human mesangial cells; however, the number of sites and the dissociation
constant value are greater than those for Ang II itself (17). These findings sug-
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gest that losartan binds not only to AT1 but also to non-Ang II receptor(s). This
Annu. Rev. Physiol. 1997.59:395-412. Downloaded from www.annualreviews.org
sites was documented in the adrenal zona glomerulosa of rats placed on a salt-
restricted diet (12). These changes in Ang II binding capacity are accompanied
by parallel changes in the transcript of the AT1 gene, the predominant Ang
II receptor in the adrenal gland. Thus dietary salt restriction increases adrenal
AT1A and AT1B mRNA by 60 and 110%, respectively (52). Of note, the Ang II
receptor number in the rat adrenal gland was shown to be up-regulated by Ang
II infusion, whereas it was down-regulated by administration of an ACEi (74).
Moreover, an infusion of Ang II in rats in vivo up-regulates AT1 mRNA without
altering its expression in other organs, and losartan administration reduces AT1
mRNA (36). Kitami et al further showed that AT1B mRNA in the rat adrenal
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receptor in the adrenal during salt restriction is, therefore, attributed to high
Ang II levels.
In contrast to these results from the rat, where Ang II leads to up-regulation
of its own receptors on glomerulosa cells and increases steroidgenic responsive-
ness, addition of this peptide to cultured bovine fasciculata and glomerulosa
cells was shown to result in both down-regulation and desensitization (67).
Moreover, in monkeys, sodium restriction causes reduction in Ang II recep-
tors in the zona glomerulosa (70). Thus the response of adrenal AT1 recep-
tors to salt restriction and Ang II appears to be different between rodents and
bovine/primate groups. One notion is that a gene duplication occurred in AT1
to produce two subtypes (i.e. AT1A and AT1B) in rodents before the species
divergence between these two groups (96) and that AT1A and AT1B in rodents
are regulated differently. Thus it appears that the different responses of the two
species groups reflect a phylogenic divergence that occurred in the regulatory
regions of the AT1 receptor genes.
Certain Gene Polymorphisms in the Renin Angiotensin
System May Significantly Impact Organ Remodeling
Processes in the Kidney and Heart
Rigat et al identified a polymorphism within intron 16 of the human ACE gene,
consisting of the presence or absence of an Alu sequence 287 bp fragment (76).
The presence of this fragment defines the insertion or the I allele, whereas its
absence defines the deletion or the D allele. This ACE genotype was thus clas-
sified as II, ID, or DD. The ACE polymorphism has a significant association
not only with the plasma level of ACE, but also with intracellular ACE as mea-
sured by ACE activity in T lymphocytes (20). Cambien et al proposed that the
ID polymorphism is a marker for increased risk of myocardial infarction (MI)
(13). Adult males with the DD genotype were found to have one-and–one-third
times the risk for MI when compared with those with other genotypes. Similar
findings have been reported by several subsequent studies (73), whereas some
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December 10, 1996 14:16 Annual Reviews MATSCHPT.TXT-CH17 AR25-17
showed variant results (10, 50). The DD genotype has also been associated
with idiopathic dilated cardiomyopathy and idiopathic ischemic cardiomyopa-
thy (73). Some studies (50) refute these observations, however.
Tiret et al found a synergistic effect of ACE ID polymorphism and angiotensin
II type 1 receptor gene polymorphism on the risk for MI (85). The polymor-
phism studied by Tiret consists of a nucleic acid substitution of A to C at position
1166 (A1166C) in the 30 untranslated region of an AT1 exon (85). A1166C ho-
mozygosity, which is, by itself, not predictive of MI, is, in a synergistic fashion
with the ACE gene DD genotype, associated with increased risk of MI. Because
this A to C substitution does not alter a potential mRNA polyadenylation or
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destabilization signal, this polymorphic locus is, as the ACE ID locus, believed
Annu. Rev. Physiol. 1997.59:395-412. Downloaded from www.annualreviews.org
also been obtained (27). Similar results were obtained in patients with diabetic
nephropathy (97).
The DD genotype was shown in preliminary studies to serve as a significant
risk factor for progressive loss of renal function in polycystic kidney disease
(31) and other renal diseases (91).
ACKNOWLEDGMENTS
Our scientific endeavors are supported by the Center of Excellence in Pediatric
Nephrology and Urology and funded by National Institutes of Health grant DK
44747. Some of the studies cited in this article were also supported in part
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Annu. Rev. Physiol. 1997.59:395-412. Downloaded from www.annualreviews.org
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