State-of-the-Art Lectures

Role of the Angiotensin Type 2 Receptor in the Regulation of Blood Pressure and Renal Function

Robert M. Carey, Zhi-Qin Wang, Helmy M. Siragy
https://doi.org/10.1161/01.HYP.35.1.155
Hypertension. 2000;35:155-163
Originally published January 1, 2000

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Abstract

Abstract—The renin-angiotensin system is a major physiological regulator of body fluid volume, electrolyte balance, and arterial pressure. Virtually all of the biological actions of the principle effector peptide angiotensin II (ANG II) have been attributed to an action at the type 1 (AT1) ANG receptor. Until recently, the functional role of the type 2 (AT2) receptor, if any, has been unknown, possibly because the AT2 receptor has a low degree of expression compared with that of the AT1 receptor. Evidence has now accumulated that the AT2 receptor opposes functions mediated by the AT1 receptor. Whereas the AT1 receptor stimulates cell proliferation, the AT2 receptor inhibits proliferation and promotes cell differentiation. These differences in growth responses have been ascribed to different cell signaling pathways in which the AT1 receptor stimulates protein phosphorylation and the AT2 receptor dephosphorylation. During the past 5 years, studies have demonstrated that the AT2 receptor is responsible for vasodilation and natriuresis, thus opposing the vasoconstrictor and antinatriuretic effects of ANG II mediated through the AT1 receptor. Work from our laboratory and others indicates that the AT2 receptor stimulates vasodilation and natriuresis by an autocrine cascade including bradykinin, nitric oxide, and cyclic GMP. The AT2 receptor also has been found to control vasodilator prostaglandins, which have a role in blood pressure regulation. The AT2 receptor appears to play a counterregulatory protective role in the regulation of blood pressure and sodium excretion that opposes the AT1 receptor.

The renin-angiotensin system is a major physiological regulator of body fluid volume, electrolyte balance, and blood pressure.1 2 3 4 However, the mechanisms by which these actions occur remain incompletely understood. The biological actions of angiotensin II (ANG II), the system’s major effector peptide, have been studied for decades and were thought to be mediated by a single ANG II receptor.1 2 3 4 In the late 1980s, however, the development of highly specific nonpeptide antagonists of the ANG II receptor (s) opened the door to the identification and pharmacological characterization of 2 major receptor subtypes, AT1 and AT2.1 2 3 4 5 6 AT1 receptors were defined as those selectively blocked by biphenylimidazoles such as losartan, whereas AT2 receptors were defined as those blocked by tetrahydroimidazopyridines, typified by PD 123319 (PD).5 6

In the first half of the 1990s, virtually all of the biological actions of ANG II were characterized by these prototype receptor antagonists as acting through the AT1 receptor, and the functions of the AT2 receptor were unknown.1 2 3 4 More recently, each of these receptors has been cloned and the signal transduction mechanisms for the AT1 and AT2 receptors have been clarified.1 2 3 4 7 8 We now have available a great deal of information concerning the receptor genes, molecular and protein structures, sites and regulation of expression, and cellular mechanisms of action.

This review will focus on the AT2 receptor, the physiological function of which was largely unclear until approximately 4 years ago, when studies began to elucidate novel physiological actions of ANG II at the AT2 receptor.9 In this review, we will emphasize the actions of ANG II mediated by the AT2 receptor that influence blood pressure and renal function. The physiological actions of ANG II at the AT2 receptor have been difficult to elicit, at least in part because the AT2 receptor has a low degree of expression in many organs, tissues, and cell types compared with that of AT1 receptors.10 11 12 13 14 15 16 However, it is now clear that although the AT2 receptor is highly expressed in fetal life and declines rapidly after birth, the receptor is expressed in the adult and participates in physiological regulation.17 18 The AT2 receptor also is reexpressed in response to injury.

General Considerations of AT2 Receptors

The molecular structure of the AT2 receptor resembles that of the superfamily of G-protein–coupled receptors containing 7 transmembrane regions.7 19 The cDNA for the AT2 receptor encodes a 363–amino acid protein (Figure 1⇓), with a molecular weight of 41 220 Da. The AT2 receptor shares only ≈34% sequence homology with the AT1 receptor.20 The gene for the AT2 receptor resides on the X-chromosome and has 3 exons with the entire coding region on the third exon.20 Promoter activity of the rat AT2 receptor gene is regulated by a number of cis-regulator domains.20 The AT2 receptor protein contains 5 potential glycosylation sites in its extracellular N-terminal tail. Among the many differences in amino acid sequence, the AT2 receptor but not the AT1 receptor has a conserved LYS199, which is important in ligand-receptor interactions. In addition, there is a potential protein kinase-C phosphorylation site in the second intracellular loop and there are 3 consensus sequences for phosphorylation by protein kinase-C and 1 phosphorylation site by cyclic AMP (cAMP)-dependent protein kinase in the C-terminal cytoplasmic tail of the receptor.2

Figure 1.
Figure 1.

Predicted 3-D structure of rat AT2 receptor based on the known amino acid sequence. The receptor has not yet been crystallized, so the actual tertiary structure is unavailable. The figure depicts the 7-transmembrane spanning regions, extracellular and intracellular domains, and the 17–amino acid sequence in the extracellular N-terminal tail, to which the polyclonal antibody described in References 17 and 18 was generated (yellow circle).

The signal transduction mechanisms for the AT2 receptor are still not well defined. The growth-inhibitory effects of the AT2 receptor are at least partially mediated by the activation of phosphotyrosine phosphatase, resulting in the inactivation of mitogen-activated protein (MAP) kinase, especially p 42 and p 44 MAP kinases, termed extracellular signal–regulated kinases (ERK).8 21 22 23 24

With respect to G-protein coupling, the data remain incomplete. Pertussis toxin attenuated AT2 receptor–mediated inhibition of ERK activity, which suggests that Gi is involved in AT2 receptor cell signaling.24 In a study of whole rat fetus, antibodies specific for Giα coselected AT2 receptor binding sites in a heterogeneous mixture of cell membranes.25 Also, transfection of the synthetic third intracellular loop peptide of the AT2 receptor into rat aortic vascular smooth muscle cells resulted in ERK inactivation, growth inhibition, and immunoprecipitation of the third loop peptide with anti-Giα antibody.22 Evidence for G-protein coupling also has come from studies in neuronal cells demonstrating that the AT2 receptor activates Gi in the modulation of K+ channels.26 27 AT2 receptors also activate MAP kinase phosphatase-1 and SHP-1 tyrosine phosphatase, a soluble tyrosine phosphatase.28 In addition, in the proximal renal tubule, AT2 receptors appear to be linked to phospholipase A2 (PLA2).29

Altogether, the evidence suggests that the AT2 receptor may be coupled to G-proteins and that the third intracellular loop may be linked with the cell signaling pathway involving Gi and ERK inactivation. However, activation of G-proteins in cell membranes by the agonist ANG II has not yet been demonstrated for the AT2 receptor, and much further work is required to define the cell signaling pathways of the receptor.

AT2 Receptor Expression and Regulation

The AT2 receptor is widely expressed in fetal tissues, but in almost all tissues there is rapid regression to low levels or disappearance of expression in the early postnatal period.10 11 12 13 14 15 16 17 18 30 31 32 33 Tissues in which AT2 receptor expression does not substantially regress and disappear in adulthood include brain, uterine myometrium, and adrenal zona glomerulosa and medulla. During fetal life, the AT2 receptor gene is expressed predominantly in areas of active mesenchymal differentiation, but the mRNA expression level decreases rapidly and disappears within days after birth.12 13 14 15 In the adult, AT2 receptor mRNA has been detected in the adrenal gland, heart, and brain.12 33 34 35 AT2 receptor mRNA is expressed in the fetal and neonatal rat kidney but disappears after the neonatal period and is not expressed in the normal adult.12 13 The same also appears to be true for heart.8

Although AT2 receptor mRNA is not expressed in adult kidney, AT2 receptor protein has been detected by immunohistochemistry and Western blot analysis with the use of a specific polyclonal antibody to the AT2 receptor in the rat kidney.17 Consistent with previous reports of AT2 receptor mRNA, receptor protein was mainly observed in the mesenchyme of fetal kidney, and receptor protein expression decreased markedly after birth.17 In the newborn kidney, AT2 receptor protein was detected in cortical glomeruli and tubule elements as well as in undifferentiated mesenchymal cells. In adult animals, renal AT2 receptor protein was present predominately in glomeruli but was markedly diminished compared with that of newborn rats. AT2 receptor protein also was found in small quantities in cortical tubules and interstitial cells in the adult.17 The AT2 receptor protein in the adult was upregulated in glomeruli, tubules, and interstitium in response to dietary sodium restriction. The mechanism of reexpression of the AT2 receptor during sodium restriction is unknown. In humans, the AT2 receptor protein is expressed in glomerular, tubular, and vascular elements (Figure 2⇓), but the regulation of receptor protein expression is unknown.

Figure 2.
Figure 2.

Immunohistochemistry of the human kidney with the use of a polyclonal antibody to the AT2 receptor. A, Positive signal is present in the glomerulus (epithelial elements) and in tubules. B, Positive signal is present in large-order renal blood vessel. C, Preabsorption control for (B) shows absence of signal.

AT2 receptor protein also has been detected in the heart by Western blot analysis and immunocytochemistry.18 AT2 receptor protein was present both in myocardium and coronary vessels throughout the ventricle and atrium of neonatal and young adult rat hearts.18 AT2 receptor protein was present only in the endothelium and not in smooth muscle cells of coronary arteries.18 By Western blot analysis, neonatal rat heart expressed significantly more AT2 receptors than young adult hearts.

Several factors regulate the expression of the AT2 receptor.17 36 37 38 39 40 41 42 43 44 ANG II, norepinephrine, insulin-like growth factor, basic fibroblast growth factor, and transforming growth factor-β all decrease AT2 receptor expression. 17 36 37 AT2 receptor expression is increased in experimental heart failure, myocardial infarction, vascular injury, and dietary sodium restriction.38 39 40 The reason for the discrepancy between the effects of ANG II and sodium restriction are unclear.

Taken altogether, the available evidence suggests that although AT2 receptor mRNA is not expressed in detectable quantities in the adult kidney, heart, and vasculature, the receptor protein is present in a site-specific distribution and may be regulated by physiological maneuvers such as sodium depletion.

General Functions of the AT2 Receptor

The AT2 receptor has several newly described functions related to cell growth, differentiation, and ultimate fate. In general, the AT2 receptor inhibits cell growth and proliferation and promotes cell differentiation, counterbalancing the opposite effects of ANG II at the AT1 receptor.45 46 47 48 Antiproliferative effects on ANG II by the AT2 receptor have been identified in several different cell types including endothelial cells, neonatal cardiomyocytes, cardiac fibroblasts, and vascular smooth muscle cells. Recent studies also suggest that the AT2 receptor inhibits angiogenesis.3 Although there is substantial evidence that the AT2 receptor mediates apoptosis, the findings remain somewhat controversial.1 2 3

The AT2 receptor has distinctive physiological actions in neuronal cells. AT2 receptors inhibit low-voltage T-type calcium channels in undifferentiated neuronal cells, which express only the AT2 subtype of angiotensin receptors.49 50 This biological action is of short duration and therefore it is possible that AT2 receptors could regulate the pacemaker activity of neuronal cells. In neuronal cells from neonatal animals, AT2 receptors activate the delayed rectifier K+ channel leading to increased cellular polarization.26 In catecholaminergic neurons, the AT2 receptor increases delayed K+ rectifier current and inhibits norepinephrine release initiated by the AT1 receptor.3 In peripheral neurons, the AT2 receptor increases a neurite-promoting protease, Nexin-1, in Schwann cells. AT2 receptor stimulation also promotes neuronal differentiation, including neurite outgrowth and upregulation of polymerized tubulin. These effects promote neuronal regeneration through the AT2 receptor.51 52 53

The AT2 receptor stimulates jejunal sodium and water absorption by a pathway that includes stimulation of the sympathetic nervous system and nitric oxide (NO) production.54 The final effector of this pathway is cyclic GMP (cGMP), which is released into the interstitial fluid on the serosal side of the transporting epithelial cells.55 This pathway opposes the actions of ANG II by the AT1 receptor to inhibit sodium and water absorption through a prostaglandin E2–dependent and cAMP-dependent mechanism.54

Role of the AT2 Receptor in Renal Function

The renin-angiotensin system plays a major role in the physiological regulation of the kidney, including the control of renal microvascular and tubular function. Before 1996, virtually all studies indicated that the renal actions of ANG II are mediated by the AT1 receptor.9 56 As discussed earlier, AT2 receptors are expressed to a low degree in the kidney compared with AT1 receptors. The predominance of renal AT1 over AT2 receptor expression in all likelihood explains past difficulty in eliciting AT2 receptor–related actions.17 44 Well-known renal actions of ANG II mediated by the AT1 receptor include increased tubular sodium absorption at low doses, inhibition of reabsorption at higher doses, afferent and efferent arteriolar vasoconstriction, and glomerular mesangial cell contraction and constriction of renal vessels, including the arcuate and interlobular arteries and vasa recta.56 57 These actions produce integrated physiological actions including decreased renal blood flow, glomerular filtration rate, and sodium excretion.

In addition to direct effects of ANG II on vascular smooth muscle and tubule cells, the peptide can stimulate the release of vasoactive factors from endothelial, vascular smooth muscle, mesangial, interstitial, or other cell types within the kidney. Thus the vascular and tubular actions of ANG II can be regulated by cell-to-cell (paracrine or autocrine) mediators produced in response to ANG II, thereby dampening or amplifying the primary effects. The most frequent integrated response to ANG II is net vasoconstriction, and the best known counteracting vasodilator mechanisms include NO and the vasodilator products of arachidonic acid metabolism, especially prostaglandin E2 (PGE2) and prostaglandin I2 (PGI2). ANG II acts directly at vascular smooth muscle cells to increase cytosolic calcium and stimulate phospholipase A2 (PLA2), which activates the formation of arachidonic acid. In this manner, it is possible for ANG II to induce renal vasodilation. ANG II increases renal NO production, which protects regional and total blood flow.58 Most of the vasodilator action of NO is through cGMP, but NO may exert some of its vasodilator action in the absence of cGMP.59 There is evidence that NO modulates the vasoconstrictor action of ANG II in the afferent but not the efferent arteriole.60 Thus there is convincing evidence that ANG II stimulates NO, which buffers the vasoconstrictor actions of ANG II.

The AT2 receptor recently has been shown to play an important role in ANG II stimulation of a number of renal vasodilator substances, including bradykinin (BK) and NO. This work was made possible by the introduction of a renal microdialysis technique that could measure small quantities of substances in renal interstitial fluid in vivo in conscious animals.61 In 1996, it was first demonstrated that the AT2 receptor antagonist PD blocked the increase in cGMP engendered by either dietary sodium restriction or exogenous ANG II administration during normal sodium intake.61 Neither of these responses were affected by the AT1 receptor antagonist losartan.61 These observations suggested that the renal AT2 receptor is stimulated to release cGMP in response to the physiological stimulus of sodium depletion. Since these renal responses are not present during normal sodium intake unless exogenous ANG II is given, the major physiological action of ANG II at the renal AT2 receptor appears to depend on activation of the endogenous renin-angiotensin system. However, the immediate increase in renal cGMP in response to ANG II in sodium-replete animals, which can be blocked completely by PD, strongly suggests that AT2 receptors are already present in the kidney and do not need to be induced or reexpressed to exert a physiological action.61

AT2 receptor–induced renal cGMP production is mediated by NO, as both the AT2 receptor antagonist PD and the NO synthase (NOS) inhibitor L-NAME blocked the increase in renal cGMP elicited by sodium restriction or exogenous ANG II.62 Since there was no additive inhibition of cGMP when PD and L-NAME were combined, the increase in renal NO is mediated by the AT2 receptor. The NOS enzyme(s) responsible for AT2 receptor stimulation of NO production appear to be multiple, including the neuronal NOS isoform.62

Because BK is also a renal autacoid that stimulates NO production63 through the B2 receptor,64 it was possible that the AT2 receptor stimulates a renal BK-NO-cGMP vasodilator cascade. In 1996, it was discovered that the renin-angiotensin system stimulates renal BK production and cGMP formation through the AT2 receptor.65 Inhibition of renin but not AT1 receptor blockade decreased markedly the elevated renal BK levels measured during sodium depletion.65 This study initiated the concept that the AT2 receptor releases BK and NO. In 1999, the ability of ANG II to stimulate BK production was confirmed.66 Exogenous ANG II increased renal BK in conscious rats, and this response was abrogated completely by PD but was not influenced by losartan.66 Neither PD nor losartan affected BK in the absence of exogenous ANG II, which suggests that activation of the renin-angiotensin system is once again required.66

The evidence cited above formed the basis for a vasodilator/natriuretic cascade (Figure 3⇓) wherein ANG II activates the AT2 receptor, resulting in the increased production of BK and NO. Alternatively, AT2 receptor stimulation could increase BK, which alone could be responsible for increasing NO and cGMP. These results have been confirmed by studies in stroke-prone spontaneously hypertensive rats, in which AT2 receptor stimulation increased aortic cGMP by increasing BK and NO formation.67

Figure 3.
Figure 3.

Schematic depiction of the regulation of blood pressure and renal function by the AT1 and AT2 receptor. PLA2 indicates phospholipase A2; COX-2, cyclooxygenase-2; BK, bradykinin; NO, nitric oxide; cGMP, guanosine 3′, 5′ cyclic monophosphate; PGE2, prostaglandin E2; PGI2, prostacyclin; and PGF2α, prostaglandin F2α.

Studies in genetically engineered mice lacking the AT2 receptor (AT2-Null) have now confirmed the concept that the AT2 receptor mediates a BK-NO-cGMP vasodilator cascade.68 These animals are essentially normotensive under basal conditions69 70 but have profound and sustained pressor and antidiuretic/antinatriuretic hypersensitivity to ANG II. AT2-Null mice were found to have very low basal renal levels of BK and cGMP.68 In response to dietary sodium restriction or exogenous ANG II for 1 week, AT2-Null failed to increase either BK or cGMP, which increased severalfold in wild-type mice (WT). Taken altogether, the evidence confirms the concept that the AT2 receptor physiologically mediates the renal production of BK and NO. These studies further suggest that the absence of the AT2 receptor and its vasodilator/natriuretic cascade is responsible for the markedly increased sensitivity of blood pressure and sodium excretion to ANG II in AT2-Null mice.

In addition to the above-mentioned mechanisms, there is evidence that an AT2 receptor located in the apical membrane of renal proximal tubule cells is linked to PLA2, whereby arachidonic acid is released and metabolized by cytochrome P450 epoxygenase.71 Recent in vitro studies demonstrate that the proximal tubule AT2 receptor is linked to inhibition of sodium and bicarbonate absorption, an effect that opposes AT1 receptor–mediated absorption.72 These studies are quite consistent with the demonstrated natriuretic role of AT2 receptors in vivo.68

Several studies have suggested a role for AT2 receptors in renal eicosanoid production and metabolism. The major renal vasodilator prostanoid is prostaglandin E2 (PGE2) and its formation occurs in response to ANG II as a result of PLA2 release of substrate arachidonic acid.73 PGE2 is formed within the kidney as a result of ANG II stimulation of the AT1 receptor.61 The possibility that the AT2 receptor might be involved in renal prostaglandin metabolism was introduced when it was shown that AT2 receptor blockade in rats on a low sodium diet increased renal PGE2.61 This increase in PGE2 could be related to an effect of the AT2 receptor on PGE2 metabolism. Prostaglandin F2α (PGF2α) can be formed directly from PGE2 by PGE2 9-ketoreductase or directly from the precursor prostanoid, PGH2. It was found that the AT2 receptor increases PGF2α formation, probably by stimulating conversion from PGE2, since the ratio of PGF2α to PGE2, a measure of such conversion, is markedly decreased with AT2 receptor blockade.74 This interpretation is consistent with the demonstrated upregulation of PGE2 9-ketoreductase by sodium depletion.75 Nonetheless, it remains possible that the AT2 receptor selectively limits the production of PGF2α but not PGE2 from PGH2.

In accord with the above observations, AT2-Null mice have increased renal PGE2 and PGI2 and decreased PGF2 both basally and in response to sodium depletion or exogenous ANG II.76 The renal vasodilator prostanoids, PGE2 and PGI2, were both stimulated by AT1 receptors, providing counterregulatory vasodilation in opposition to the AT1 receptor–mediated vasoconstrictor action of ANG II. In addition, very high renal cAMP levels in AT2-Null compared with WT were normalized by blockade of the AT1 receptor, which reduced PGE2 and PGI2 to low levels.76 This raises the likelihood that these vasodilator prostanoids act physiologically through stimulation of adenylyl cyclase and cAMP production. Figure 3⇑ summarizes the effects of AT1 and AT2 receptors on renal prostaglandin production and metabolism.

There also is evidence that the AT2 receptor mediates vasodilation in the rabbit afferent arteriole through a cytochrome P-450 pathway, possibly by means of epoxyeicosatetraenoic acid.77 Activation of the AT2 receptor modulates AT1 receptor–mediated vasoconstriction in the afferent arteriole of the spontaneously hypertensive rat.78 The vasodilator action of ANG II stimulation of the AT2 receptor in these direct vascular studies confirms the results of the studies in vivo.

The net effect of ANG II on renal function is a combination of AT1 and AT2 receptor–mediated events with the AT1 receptor–mediated effects generally predominant. Thus ANG II administration results in net renal vasoconstriction and reduced glomerular filtration. These effects are modulated, however, by AT2 receptor–stimulated BK, NO, and cGMP. The net sodium excretory response to ANG II depends on its concentration: Low concentrations inhibit sodium excretion, whereas higher concentrations induce natriuresis. At this time, we are still unsure which receptor mediates the natriuretic response to high concentrations of ANG II.

Role of the AT2 Receptor in Control of Blood Pressure

As discussed earlier, AT2-Null mice have slightly elevated blood pressures compared with WT, but still well within the normotensive range.68 69 70 74 Stimulation with exogenous ANG II, either acutely or chronically, increases blood pressure to a much greater extent in AT2-Null than WT. AT2-Null infused with a low dose of ANG II (4 pmol/kg per minute) that does not affect blood pressure in WT increases blood pressure substantially into the hypertensive range in AT2-Null.68 This increase in blood pressure response to ANG II in the absence of the AT2 receptor is accompanied by deficiency of the BK-NO-cGMP vasodilator cascade, the absence of which causes the ANG II hypersensitivity. A possible additional reason for the ANG II hypersensitivity may be upregulation of AT1 receptors triggered by AT2 receptor deficiency.79 80 However, AT1 receptor upregulation would not account for the deficiency of vasodilator autacoids in this model.

The elevation of PGE2 and PGI2 in AT2-Null suggested the possibility that these vasodilator prostanoids might prevent hypertension in this model. Reduction of PGE2 and PGI2 with indomethacin, a cyclooxygenase inhibitor, resulted in a progressive and sustained increase in blood pressure well into the hypertensive range in AT2-Null while having no effect on blood pressure in WT.76 Therefore, in AT2-Null, increased vasodilator prostanoids prevent hypertension that otherwise would accompany the hypersensitivity of blood pressure and sodium excretion to ANG II. This is an unusual example of the vasodilatory capacity of prostanoids in physiology.

The BK-NO-cGMP vasodilator cascade mediated by the AT2 receptor suggested the possibility that the AT2 receptor may subserve a protective role in blood pressure regulation. In a 2-kidney, 1-wrap model of renal vascular hypertension, activation of the renin-angiotensin system increases blood pressure through the AT1 receptor. Blood pressure reduction with AT1 receptor blockade with losartan was prevented by AT2 receptor blockade with PD and by use of the BK-B2 receptor antagonist icatibant.66 Similar data are available for 2-kidney, 1-clip Goldblatt hypertensive animals (Carey, unpublished observations). Thus the AT2 receptor engenders counterregulatory vasodilation and protects against a further increase in blood pressure in these models of angiotensin-dependent hypertension. Abrogation of the hypotensive action of AT1 receptor blockade with AT2 receptor inhibition suggests that at least some of the beneficial effects of AT1 receptor blockade are mediated by the AT2 receptor, possibly by the BK-NO-cGMP vasodilator cascade.

In the 2-kidney, 1-wrap model of angiotensin-dependent hypertension, the vasodilator autacoids BK, NO, and cGMP were markedly decreased in the ischemic kidney and augmented in the contralateral kidney.66 The increase in vasodilator autacoids in the contralateral kidney was due to AT2 receptor stimulation, since these were inhibited to control levels with PD.66 In the ischemic kidney, the AT1A receptor protein was downregulated in both kidneys, whereas the AT2 receptor was downregulated only in the ischemic kidney.44 Therefore the protective effect of the AT2 receptor is probably mediated by augmentation of a BK-NO-cGMP vasodilator cascade in the contralateral, nonischemic kidney, in which AT2 receptor expression is maintained.

In parallel with studies of angiotensin-dependent hypertension, investigators have demonstrated a role for the AT2 receptor in the regulation of blood pressure in normal salt-restricted rats.81 82 In salt-restricted rats, AT2 receptor blockade with PD was found to offset the blood pressure–lowering effect of losartan or valsartan, which suggests that AT1 receptor blockade lowers blood pressure, at least in part, by stimulation of AT2 receptors caused by increased ANG II.81 82 AT1 receptor blockade in these animals was associated with an increase in renal BK, NO, and cGMP.82 AT2 receptor blockade with PD inhibited both the hypotension and the renal responses of BK, NO, and cGMP to valsartan, confirming that during AT1 receptor blockade there is concomitant stimulation of the AT2 receptor. Furthermore, the increase in renal NO and cGMP during AT1 receptor blockade appears to be mediated by BK because BK-B2 receptor blockade inhibited this response (H.M.S., M. deGasparo, and R.M.C., unpublished data, 1999).

The discovery that the AT2 receptor mediates a BK-NO-cGMP vasodilator cascade61 62 65 66 67 68 has recently been confirmed in mice overexpressing the AT2 receptor selectively in vascular smooth muscle cells.82 In this study, AT2 receptor expression was increased from low levels (7.5%) to ≈39% of the expression of the AT1 receptor.82 Animals with AT2 receptor overexpression were normotensive. However, pressor responses in vivo and vasoconstriction in vitro to ANG II were absent in animals overexpressing the AT2 receptor. In animals overexpressing the AT2 receptor, vasoconstrictor responses to ANG II were restored with AT2 receptor blockade and also with BK-B2 receptor blockade or with NOS inhibition. The initiating event was proposed as AT2 receptor activation of kininogenase through cellular acidification to induce BK production,82 but the early part of the pathway requires further study. This study82 is consistent with a protective role of the AT2 receptor in blood pressure regulation and confirms the earlier discovered vasodilator paracrine mechanism of AT2 receptor action via BK, NO, and cGMP.

The role of the AT2 receptor in pressure-natriuresis has been controversial. Several studies from Sassard’s group have indicated that pressure-natriuresis is inhibited by the AT2 receptor.83 84 The majority of reports, however, indicate that the AT2 receptor stimulates pressure-natriuresis.66 68 85 In rats with 2-kidney, 1-wrap renovascular hypertension, pressure-natriuresis in the nonischemic kidney is accompanied by maintenance of AT2 receptor expression and an increase in AT2 receptor–dependent BK, NO, and cGMP.66 In AT2-Null mice, an increase in pressure with ANG II is accompanied by a sustained antinatriuresis.68 Also, AT2-Null mice have their pressure-natriuresis curves shifted rightward in association with reduced renal cortical and medullary blood flow.85 Resolution of these differences is important because virtually all hypertensive processes are accompanied by a reduction in pressure-natriuresis resulting in renal sodium retention.86

Figure 4⇓ summarizes the role of AT1 and AT2 receptors in blood pressure regulation.

Figure 4.
Figure 4.

Schematic illustration of the overall role of AT1 and AT2 receptors in blood pressure regulation.

Opposing Actions of AT1 and AT2 Receptors

As is true for other peptide receptor families, the interaction between receptor subtypes within a family may be important to the physiological response to the agonist. In general, ANG II effects at the AT1 receptor are opposed by actions at the AT2 receptor. This principle applies to neuronal effects, actions on cell proliferation and differentiation, angiogenesis, and chronotropic effects in the heart.30 87 88 89 90 91 In the skin, ANG II binding to AT1 receptors increases inositol phosphate production, whereas ANG II inhibits inositol phosphate production by the AT2 receptor.92 In the gastrointestinal tract, AT1 receptors oppose AT2 receptors in sodium and water absorption, and there is clear physiological opposition between these receptors as sodium transport is finely tuned.54

In the kidney, the AT1 receptor induces vasoconstriction and sodium retention, whereas the AT2 receptor promotes vasodilation and natriuresis.66 68 72 AT2 receptor blockade prevents the hypotensive effects of AT1 receptor blockade and the AT2 receptor mediates the depressor response to ANG II.66 79 80

In general, the AT1 receptor stimulates protein phosphorylation and the AT2 receptor stimulates protein dephosphorylation, which counterbalances the effects of protein kinases, especially MAP kinase, stimulated by the AT1 receptor. Figure 5⇓ indicates the role of AT2 receptors in counterbalancing the actions of AT1 receptors.

Figure 5.
Figure 5.

Schematic depiction of the balance of actions mediated by AT1 and AT2 receptors. AT1 receptor actions are shown on the left and counterbalancing actions of AT2 receptors on the right.

Conclusions

The past 5 years have witnessed a dramatic change in the way we view the renin-angiotensin system. Until recently, the vascular and renal actions of ANG II were thought to be transduced solely through the AT1 receptor, and the function of the AT2 receptor was unknown. However, recent information has emerged in support of a role for the AT2 receptor in the regulation of blood pressure and kidney function. The AT2 receptor mediates a vasodilator/natriuretic renal autacoid cascade that includes BK, NO, and cGMP. This pathway is important as a counterregulatory mechanism opposing the vasoconstrictor/antinatriuretic actions of ANG through the AT1 receptor and plays a protective role in renal vascular hypertension. The AT2 receptor also modulates renal prostaglandins, which play an important role in blood pressure regulation. Further studies in AT1 and AT2 receptor–deficient animals will help clarify these mechanisms. From the actions described for the AT2 receptor thus far, one would logically predict that a specific AT2 receptor agonist may have beneficial and protective advantages in the treatment of hypertension and renal and cardiovascular disease.

  • Received September 13, 1999.
  • Revision received October 1, 1999.
  • Accepted November 8, 1999.

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  • Role of the Angiotensin Type 2 Receptor in the Regulation of Blood Pressure and Renal Function
    Robert M. Carey, Zhi-Qin Wang and Helmy M. Siragy
    Hypertension. 2000;35:155-163, originally published January 1, 2000
    https://doi.org/10.1161/01.HYP.35.1.155
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