ANGIOTENSIN II RECEPTOR SUBTYPES

The development of highly specific and selective AT₁ receptor antagonists, such as losartan, valsartan, eprosartan, irbesartan, candesartan, telmisartan, and others^5,6, and AT₂ receptor ligands/antagonists, such as PD123177, PD123319, and CGP42112^6,7, was the basis for the identification and characterization of Ang II receptor subtypes. Two main Ang II receptor subtypes have been characterized, AT₁ and AT₂, which are heterogeneously distributed in peripheral tissues and in the brain Table 1^5,8,9,10. In humans, only a single gene encoding for the AT₁ receptor is expressed, which is localized on chromosome 3. In rodents, however, AT_1a and AT_1b receptor isoforms exist, which are localized on chromosomes 17 and 2, respectively. They show 91% similarity for nucleic acid and 96% similarity for amino acids^11,12. Although AT_1a and AT_1b subtypes seem to be more or less equally expressed in spleen, liver, and kidneys^4,11,12, the AT_1a receptor seems to predominate in VSM, heart, lung, ovary, and hypothalamus^{4,11,12,13,14}. The fact that AT_1a predominates in VSM suggests that this subtype plays a role in vasoconstriction. On the other hand, as the AT_1b receptor subtype seems to prevail in the anterior pituitary, adrenal gland, uterus, and several periventricular brain areas^{4,12,13,14,15}, this receptor may be involved in hormonal secretion and central osmotic control. In humans and mice, the genes for the AT₂ receptor are localized on the X-chromosome. Both AT₁ and AT₂ receptors belong to the seven-transmembrane-domain superfamily of receptors, but the nucleic acid sequence of the AT₁ receptor has only 34% identity with the AT₂ receptor sequence. The AT₂ receptor is found ubiquitously in fetal tissues. In the adult organism, this receptor is expressed highly in the adrenal medulla, uterus, and ovary, and is also found in vascular endothelium and certain areas of the brain^4,10,16,17. The fact that the AT₂ receptor is expressed at high levels in embryonic tissues but much less so in normal adult tissues has prompted speculation on its possible role in cell growth and differentiation. The presence of different subtypes for the AT₂ receptor and the existence of AT₃ and AT₄ receptor subtypes are still controversial^{18,19,20,21,22,23}.

Table 1 - AT₁ and AT₂ receptors and their distribution.

Full table (36K)

THE AT₁ RECEPTOR

The AT₁ receptor reportedly interacts with various G proteins and is coupled to one of the two heteromeric G proteins: G_q or G_i. Ang II binding to specific sites of the extracellular and membrane-spanning portions of the AT₁ receptor releases the subunit of the G protein and subsequently activates phospholipase C via G_q or inhibits adenylate cyclase via G_i. Phospholipase C activation generates 1,4,5-inositol trisphosphate and diacylglycerol, with subsequent activation of protein kinase C and an increase in intracellular [Ca²⁺] via L-type Ca²⁺ channels^24,25,26. The rise in intracellular [Ca²⁺] is accompanied by typical AT₁ receptor-associated responses such as vasoconstriction, renal salt and water retention, aldosterone and vasopressin release, effects on glomerular filtration rate, and renal blood flow, as well as the Ang II-mediated stimulation of cell growth. Protein kinase C and elevated intracellular [Ca²⁺] promote expression of growth-related inducible transcription factors, such as, c-fos, c-myc, and c-jun²⁷. The proteins encoded by the growth-related inducible transcription factors act as transcription factors for various target genes, which may be involved in the stimulation of mitogenesis. Ang II also induces, via the AT₁ receptor, transcription of platelet-derived growth factor-A chain and transforming growth factor-₁ and so is coupled directly to growth factor expression^28,29. It was shown recently that stimulation of AT₁ receptors in VSMcells (VSMCs) induces rapid phosphorylation of tyrosine in the intracellular kinases Jak2 and Tyk2 and that this phosphorylation is associated with increased Jak2 activity³⁰. This is significant, because the Jak-STAT pathway may be the signaling mechanism used by cell surface-binding cytokines responsible for transcriptional activation of early growth response genes³¹. This pathway may thus play an additional role in the control of AT₁-mediated cell growth.

VSMCs in culture, a cell line commonly used for studying trophic effects of Ang II, express only AT₁ receptors, and consequently, trophic effects shown in these cells can be mediated only by AT₁ receptors¹⁷. In all experiments on these cells, AT₂ receptor ligands are ineffective. The growth responses of VSMCs to Ang II vary with the particular VSMC studied, and the mechanisms leading to differential growth responses are still controversial. Dzau et al have proposed that Ang II represents a bifunctional growth factor for VSMCs by simultaneously stimulating proliferative and antiproliferative pathways that appear to be mediated by the activation of platelet-derived growth factor-AA and transforming growth factor-₁, respectively, thereby shifting the balance in favor of hypertrophy instead of hyperplasia in some instances³².

Compared with AT₂ receptors, AT₁ receptors dominate by far in the adult human³³ and rat³⁴ kidneys; only 5% to 10% of the Ang II receptors are AT₂. This predominance of AT₁ receptors might in part explain why angiotensin converting enzyme (ACE) inhibitors and AT₁ antagonists act very similarly in the kidney³⁵. AT₁ antagonists can also vasodilate the renal vessels, particularly the glomerular efferent (and afferent) arterioles, increase cortical renal plasma flow^36,37, and enhance glomerular filtration rate via a contraction of mesangial cells. Beneficial effects, in extent comparable to those of ACE inhibitors, on proteinuria, microproteinuria, and diabetes-induced changes of the kidney have also been described for AT₁ antagonists³⁸, and in spontaneously hypertensive rats, AT₁ antagonists improve cardiac and vascular structure and function similar to ACE inhibitors³⁹.

In newborn rat kidneys, AT₁ mRNA occurs in glomeruli, vessels, and nephrogenic cortex, areas where cell proliferation and differentiation occur simultaneously. Blockade of the AT₁ receptor in newborn rats arrests nephrovascular maturation and renal growth, resulting in altered kidney architecture, characterized by fewer, thicker, and shorter afferent arterioles, reduced glomerular size and number, and tubular dilation¹. When the mouse AT_1a receptor gene is disrupted in embryonic stem cells (AT₁ knockout), however, the deletion is not lethal, and mice are born in expected numbers with normal vasculature, kidneys, and hearts but significantly lower blood pressure⁴⁰. This suggests that the effects of AT₁ receptor blockade on renal structure and function might not only be due to blockade of the AT₁ receptor itself. Actions of the unopposed AT₂ receptor may contribute, as AT₁ receptor antagonists do not affect the AT₂ receptor (and potentially other angiotensin receptor subtypes) but even expose it to increased Ang II levels. The latter is due to the loss of the negative feedback exerted by Ang II via the AT₁ receptor on renin release, and hence on its own generation. It is thus conceivable that under blockade of AT₁ receptors, Ang II interactions with other unopposed Ang II receptors, such as AT₂, are intensified, contributing to the beneficial effects on cardiac and vascular structure seen with AT₁ antagonists^17,41.

THE AT₂ RECEPTOR

In contrast to the AT₁ receptor, much less is known about the structural and functional properties of the AT₂ receptor. Although this Ang II receptor subtype has been cloned recently^42,43, its molecular structure and signal transduction pathway are far from completely understood. The rat AT₂ receptor cDNA encodes for a 363-amino acid protein that has a seven-transmembrane topology and 34% homology in nucleic acid sequence to the AT₁-receptor. However, it is still controversial whether the AT₂ receptor is coupled to G proteins and how it signals. Kambayashi et al have reported that the rat AT₂ receptor inhibits a phosphotyrosine phosphatase in COS-7 cells stably expressing the rat AT₂ receptor⁴². This effect is dependent on a pertussis-toxin—sensitive, G-protein—coupled mechanism. Further evidence in support of AT₂ receptor coupling to G proteins has been provided by Kang et al who have shown that G_i (but not G_o) is involved in AT₂ receptor-mediated modulation of K⁺ channels in rat primary cultures of neuronal origin⁴⁴. On the other hand, Mukoyama et al have reported that the rat AT₂ receptor shares a seven-transmembrane domain topology that may belong to a unique class of seven-transmembrane receptors for which G-protein coupling has not been demonstrated⁴³. In their studies, stimulation of the cloned AT₂ receptor, transiently expressed in COS-7 cells, failed to increase 1,4,5-inositol trisphosphate or intracellular [Ca²⁺], and no apparent effects on cAMP and cGMP levels or phosphotyrosine phosphatase activity could be observed. In NG 108-15 cells, which express AT₂ receptors constitutively, AT₂ receptor stimulation inhibits T-type Ca²⁺ channels through an as yet undefined pathway²⁶. In another cell line, PC12W, which only expresses AT₂ receptors, Ang II stimulates a membrane-associated phosphotyrosine phosphatase and inhibits atrial natriuretic peptide-sensitive particulate guanylate cyclase via a G-protein—independent pathway^28,45.

The relationship between AT₂ receptor-mediated signaling and tyrosine phosphorylation^42,45 and the fact that the AT₂ receptor subtype is highly and transiently expressed in fetal tissues followed by a dramatic decrease in most organs just after birth⁴⁶ suggests that this receptor plays a role in physiological processes involving cellular growth, differentiation, and adhesion. Recent studies in our laboratory demonstrate that angiotensin peptides can exert an antimitogenic action on rat and bovine endothelial cells of different origin via the AT₂ receptor, suggesting that Ang II has different growth-modulating actions depending on the presence or absence of Ang II receptor subtypes on a given cell^17,47,48. In further studies in PC12W cells, we also demonstrated that Ang II inhibits fetal calf serum- and epidermal growth factor-induced proliferation and potentiated nerve growth factor- and epidermal growth factor-mediated growth inhibition via the AT₂ receptor^41,49,50. This effect is obviously not AT₂-mediated, as c-fos and c-jun mRNA expression are not inhibited through the AT₂ receptor⁵¹. Our results are supported by recent findings by Nakayima et al⁵² who have attempted to characterize the role of the AT₂ receptor in the model of neointima formation in the balloon-injured rat carotid artery. In this in vivo gene transfer study, the AT₂ receptor was transfected to the injured vessel, and the formation of neointima was studied in the presence or absence of the AT₂ receptor. Morphometric analysis performed 14 days after balloon injury revealed that myointimal size was reduced by 70% in the presence of the AT₂ receptor. This effect could be reversed by the AT₂ antagonist PD 123319, suggesting that the expressed AT₂ receptor mediated the inhibiting effect on neointima formation.

Siragy and Carey⁵³ recently have reported that prostaglandin E₂ (PGE)₂ and cGMP levels in the renal interstitial fluid were not altered by AT₁ and/or AT₂ receptor blockade during normal sodium intake in rats. However, under conditions of sodium depletion, the AT₂ antagonist PD123319 inhibited the increase in cGMP engendered by dietary sodium. Treatment with the AT₁ antagonist losartan had no effect on cGMP but significantly decreased PGE₂, whereas PD123319 further increased PGE₂ levels. A combined blockade with losartan and PD123319 decreased both PGE₂ and cGMP. These findings suggest that under conditions of a stimulated renal RAS, but not under normal conditions, the AT₁ receptor promotes renal production of PGE₂, whereas the AT₂ receptor mediates cGMP production. These data imply an interaction between AT₁ and AT₂ receptors with respect to the production and release of these intermediators. These findings are supported by data obtained in spontaneously hypertensive rats, in which AT₂ receptor-mediated stimulation of the bradykinin/nitric oxide system can account for effects of AT₁ receptor blockade on aortic cGMP⁵⁴. Postnatal blockade of AT₂ receptors in newborn rats does not alter nephrovascular growth or maturation³, a finding consistent with AT₂ receptors being abundant during fetal life but disappearing soon after birth^46,55,56. Along these lines, AT₂ mRNA in rat kidney is expressed in undifferentiated nephrogenic mesenchymal tissue but not in the immature and mature glomeruli and tubules from day 12 of fetal life to day 15 postpartum, disappearing totally after day 22 postpartum^55,57. However, AT₂ receptors can be reexpressed under pathophysiological conditions involving tissue remodeling or repair, such as in vascular neointima formation, postmyocardial infarction, or nerve injury as well as apoptosis^4,58, to control excessive growth mediated via the AT₁ receptor or by other growth factors. These findings, together with the fact that the AT₂ receptor exerts growth-inhibiting effects on neuronal and endothelial cells^17,41 and displays a growth-dependent regulation in cultured rat mesangial cells⁵⁹, suggest that the AT₂ receptor has general significance for cell growth and differentiation.

SUMMARY

The characterization of the Ang II receptor subtypes offers new tools to advance knowledge on the various functions of Ang II. Recently, AT₁ receptor antagonists have been introduced as orally active antihypertensive drugs. They block AT₁ receptors specifically with low toxicity and high therapeutic safety, and improve cardiac and vascular structure and function similarly to ACE inhibitors. The mechanisms for these additional effects of AT₁ blockers are not yet understood. Besides blood pressure reduction, blockade of the AT₁ receptor may prevent the hypertrophic effects of Ang II with the help of the AT₂ receptor. Furthermore, we could show that Ang II also exerts differential growth-modulating actions depending on the presence or absence of the receptor subtypes on a given cell. Stimulation of AT₁ receptors results in cell growth and/or proliferation, whereas stimulation of AT₂ receptors inhibits cell proliferation. Moreover, there is evidence that AT₁ and AT₂ receptors counteract each other by an as yet unknown mechanism with respect to cell proliferation and differentiation.

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