Angiotensin II type 2 receptors in the kidney: evidence for endothelial-cell-mediated renal vasodilatation

Shuji Arima and Sadayoshi Ito

The Second Department of Internal Medicine, Tohoku University School of Medicine, Sendai, Japan

Correspondence and offprint requests to: Shuji Arima MD, The Second Department of Internal Medicine, Tohoku University School of Medicine, 1–1 Seiryo-cho, Aoba-ku, Sendai, 980–8574, Japan.

Introduction

Angiotensin II (Ang II), the physiologically active component of the renin–angiotensin system, plays an important role in the regulation of the cardiovascular and renal systems. Based on their different pharmacological and biochemical properties, two distinct subtypes of Ang II receptor have been defined and designated as type 1 (AT1) and type 2 (AT2) receptors. While both AT1 and AT2 receptors belong to the seven-transmembrane, G-protein-coupled receptor family, the function and signalling mechanism of these receptor subtypes are quite different [1,2]. Extensive pharmacological evidence indicates that most of the well-characterized actions of Ang II (such as vasoconstriction, cell proliferation, and renal salt retention) are now generally considered to result from stimulation of AT1 receptors [1,2], whereas the functional role of AT2 receptor has not been well defined. However, recent studies suggest that the AT2 receptors exert the opposite effects of AT1 receptors in terms of cardiovascular haemodynamics and cell growth. For example, the activation of AT2 receptors exerts antigrowth, antihypertrophic, proapoptotic [3], and hypotensive effects [4]. In the kidney, activation of the AT2 receptor has been reported to regulate pressure-natriuresis [5] and to stimulate the production of nitric oxide (NO) and bradykinin [68], which may cause renal vasodilatation. We have also demonstrated that in the renal microvasculature activation of AT2 receptor causes endothelium-dependent vasodilatation, which modulates the vasoconstrictor action mediated by the AT1 receptor [9]. In this article, we will summarize results obtained from recent studies on the AT2 receptor-mediated action of Ang II in the kidney, together with other relevant literature. Only a limited number of references are given.

AT2-receptor-mediated action of Ang II in the kidney

The renal distribution of the AT2 receptor and its mRNA shows remarkable species differences and is most prominent in fetal and newborn mammalian kidneys. High levels of AT2 receptors and mRNA expression have been demonstrated in the macula densa of ovine fetal kidney, suggesting a potential role of AT2 receptors in the development of this structure [10]. Nishimura et al. [11] also reported the involvement of AT2 receptors in the formation of the embryonic ureter by the promotion of the mesenchymal cell apoptosis. In contrast, the expression of AT2 receptors in the adult mammalian kidney has been reported to be very low, and localized mainly in the glomerular mesangial cells [12,13] or adventitia of the preglomerular arcuate and interlobular arteries [14]. However, recent functional studies have demonstrated that some part of the Ang II action on the kidney is mediated by AT2 receptors. Using a microdialysis technique, Siragy and Carey [6,7] have demonstrated that the renal AT2 receptors may be activated during sodium depletion or Ang II administration in the conscious adult rat and that the AT2 receptor mediates renal interstitial production of NO and bradykinin, leading to increased cGMP levels in the renal interstitial fluid. In addition, studying with adult AT2 receptor-null mutant mice, they found that the AT2 receptor plays a counter-regulatory protective role against the AT1 receptor-mediated antinatriuretic and pressor actions of Ang II and that this protective action of the AT2 receptor is mediated by bradykinin and NO [8]. They also found that the AT2 receptor decreases renal interstitial prostaglandin E2 (PGE2) level by stimulating its conversion to PGF2{alpha} by 9-ketoreductase [6,15].

These observations suggest that the renal AT2 receptor may be re-expressed in the adult kidney in response to Ang II and may mediate renal vasodilatation and/or inhibition of tubular sodium reabsorption by stimulating bradykinin, NO, and/or eicosanoid production. However, a potential renal tubular action of the AT2 receptor is still controversial. Lo et al. [16] isolated tubular function from haemodynamic action by maintaining a constant renal blood flow and found that blockade of the AT2 receptor markedly and rapidly increased diuresis and natriuresis from the rat kidney. Madrid et al. [5] also observed that activation of the NO/cGMP system by AT2 receptor impaired pressure diuresis. These studies indicate the possibility of renal sodium retention by AT2 receptors. In marked contrast, Haithcock et al. [17] recently demonstrated that the proximal tubular AT2 receptor is linked to inhibition of bicarbonate reabsorption, an effect that opposes AT1 receptor-mediated facilitation of sodium and bicarbonate reabsorption. Further studies examining the tubular action of AT2 receptor (whether natriuretic or antinatriuretic) are clearly required.

Vasodilator action of AT2 receptors in renal microvessels

Ichiki et al. [4] and Siragy et al. [8] recently demonstrated that AT2 receptor null mutant mice have a higher blood pressure and exert an enhanced pressor response to exogenously infused Ang II compared to the wild-type control. In addition, as mentioned above, several studies have demonstrated that the AT2 receptor stimulates bradykinin, NO, and/or eicosanoid production in the kidney. Taken together, these findings suggest that the renal AT2 receptor mediates vasodilatation and plays an important role in the control of blood pressure. To test this possibility, we examined whether selective activation of AT2 receptor causes vasodilatation in the afferent arteriole (Af-Art) [9], a vascular segment that accounts for most of the preglomerular resistance. We microperfused rabbit Af-Arts at 60 mmHg in vitro, and examined the effect of Ang II on the luminal diameter.

We found that (i) blockade of AT1 or AT2 receptor abolishes or augments the Ang II-induced vasoconstriction in Af-Arts, respectively; (ii) in preconstricted Af-Arts treated with an AT1 receptor antagonist, Ang II now causes dose-dependent dilatation, which is abolished by AT2 receptor blockade; (iii) the dilatation was unaffected by inhibiting the synthesis of NO or prostaglandins, however, it was completely abolished by either disrupting the endothelium or inhibiting the synthesis of epoxyeicosatrienoic acids (EET).

Our results demonstrate for the first time that in the renal resistance arterioles, activation of the AT2 receptor induces endothelium-dependent and EET-mediated vasodilatation, which modulates the vasoconstrictor action of Ang II-mediated by the AT1 receptor. Figure 1Go shows an example of AT2 receptor-mediated dilatation of Af-Art (left) and its blockade by EET synthesis inhibition (right). Similar findings (activation of AT2 receptor induces vasodilatation and modulates the vasoconstrictor action of Ang II mediated by AT1 receptor) were also obtained in the postglomerular efferent arterioles [18], another crucial vascular segment to the control of glomerular haemodynamics.



View larger version (117K):
[in this window]
[in a new window]
 
Fig. 1. Ang-II-induced dilatation of Af-Art pretreated with CV and NE (left) and its blockade by miconazole (right). (Left) Af-Artspretreated with CV (10-8 M) and NE (0.5 µM); (right) Af-Arts pretreated with CV, NE, and miconazole (10-6 M). Note that Ang IIdilated preconstricted Af-Arts pretreated with CV, and the dilatation was abolished by miconazole. CV (CV11974), a specific AT1 receptorantagoist; NE, norepinephrine; miconazole, an EETs synthesis inhibitor. (Reproduced from reference [9] by permission of the publisher.).

 
Our findings that EETs but not NO synthesis inhibition diminishes AT2 receptor-mediated vasodilatation in Af-Arts suggest that activation of AT2 receptor stimulates EETs but not NO release in Af-Arts. This notion is supported by the findings of Thorup et al. [19] that in renal resistance arteries, Ang II stimulates endothelial NO release through AT1 receptors. In contrast, Siragy and Carey [6,7] suggested that renal AT2 receptors are coupled to the NO/bradykinin pathway, which plays a counter-regulatory protective role against the AT1 receptor-mediated pressor actions of Ang II [8]. The reason for this discrepancy between our results and theirs is unclear; however, it may be related to the origin of NO measured in their study. Within the kidney NO is produced not only by the vascular endothelium but also by several tubular segments including the macula densa [20,21]. Thus, it is possible that activation of the AT2 receptor stimulates the production of EETs in vascular endothelial cells and that of NO/bradykinin in several cell types other than vascular endothelial cells. Further studies examining the renal vascular actions of AT2 receptors (together with the mechanism underlying) in whole kidney levels are clearly required.

Renal AT2 receptors under pathological conditions, and concluding remarks

Several recent studies have reported the possibility that impaired function of renal AT2 receptors may play an important role in various physiological and pathological conditions. Goto et al. [13] reported that cultured mesangial cells, prepared from stroke-prone spontaneously hypertensive rats (SHRSP), showed lower expression of AT2 receptors and higher proliferation activity as compared to those of normotensive Wistar–Kyoto rats (WKY). This suggests that AT2 receptors may exert an antiproliferative effect in mesangial cells. Consistent with these findings, accelerated renal interstitial fibrosis and collagen deposition has been observed in adult AT2 receptors null mutant mice during unilateral obstruction [22]. In addition, antihypertensive effects of the renal AT2 receptor have also been demonstrated. Siragy and Carey [23] recently demonstrated that the AT2 receptor, by stimulating the renal interstitial release of bradykinin and NO, prevents a further increase in blood pressure in a rat renovascular hypertension model. They also found that in the absence of AT2 receptor, conversion from PGE2 to PGF2{alpha} is decreased and that increased vasodilator PGs (PGE2 and PGI2) protect against the development of hypertension [24]. We have also demonstrated that vasoconstrictor action of Ang II is exaggerated in Af-Arts of SHR due to an impaired function of the AT2 receptor before the development of hypertension [25]. Since an exaggerated response of Af-Arts to Ang II is thought to be responsible, at least in part, for the elevated renal vascular resistance (which is important for development and maintenance of hypertension), our findings suggest that impaired function of the AT2 receptor in Af-Arts may play a role in the development and maintenance of hypertension in SHR.

From these studies, it has now become obvious that AT2 receptors play some important roles in the pathogenesis and remodelling of renal and cardiovascular diseases including hypertension. Thus, AT1 receptor antagonists, newly developed and already available antihypertensive drugs, may exert their renoprotective and antihypertensive effects partly through AT2 receptor activation, because treatment with AT1 receptor antagonists elevates plasma levels of Ang II [26], which preferentially binds to AT2 receptor. Further understanding of the renal AT2 receptor function may contribute to new therapeutic strategies of AT1 receptor antagonists for renal diseases and hypertension.

References

  1. Matsubara H. Pathophysiological role of angiotensin II type 2 receptor in cardiovascular and renal diseases. Circ Res 1998; 83: 1182–1191[Abstract/Free Full Text]
  2. Horiuchi M, Akishita M, Dzau VJ. Recent progress in angiotensin II type 2 receptor research in the cardiovascular system. Hypertension 1999; 33: 613–621[Abstract/Free Full Text]
  3. Nakajima M, Hutchinson H, Fujinaga M et al. The angiotensin II type 2 (AT2) receptor antagonizes the growth effects of the AT1 receptor: gain-of-function study using gene transfer. Proc Natl Acad Sci USA 1995; 92: 10663–10667[Abstract]
  4. Ichiki T, Labosky PA, Shiota C et al. Effects on blood pressure and exploratory behavior of mice lacking angiotensin II type-2 receptor. Nature 1995; 377: 748–750[ISI][Medline]
  5. Madrid MI, Garcia-Salom M, Tornel J, Gasparo MD, Fenoy FJ. Effect of interactions between nitric oxide and angiotensin II on pressure diuresis and natriuresis. Am J Physiol 1997; 42: R1676–1682
  6. Siragy HM, Carey RM. The subtype-2 (AT2) angiotensin receptor regulates renal cyclic guanosine 3',5'-monophosphate and AT1 receptor-mediated prostaglandin E2 production in conscious rats. J Clin Invest 1996; 97: 1978–1982[Abstract/Free Full Text]
  7. Siragy HM, Carey RM. The subtype 2 (AT2) angiotensin receptor mediates renal production of nitric oxide in conscious rats. J Clin Invest 1997; 100: 264–269[Abstract/Free Full Text]
  8. Siragy HM, Inagami T, Ichiki T, Carey RM. Sustained hypersensitivity to angiotensin II and its mechanism in mice lacking subtype-2 (AT2) angiotensin receptor. Proc Natl Acad Sci USA 1999; 96: 6506–6510[Abstract/Free Full Text]
  9. Arima S, Endo Y, Yaoita H et al. Possible role of P-450 metabolite of arachidonic acid in vasodilator mechanism of angiotensin II type 2 receptor in the isolated and microperfused rabbit afferent arteriole. J Clin Invest 1997; 100: 2816–2823[Abstract/Free Full Text]
  10. Butkus A, Albiston A, Alcorn D et al. Ontogeny of angiotensin II receptors, type 1 and 2, in ovine mesonephros and metanephros. Kidney Int 1997; 52: 628–636[ISI][Medline]
  11. Nishimura Y, Yerkes E, Hohenfellner K et al. Role of the angiotensin type 2 receptor gene in congenital anomalies of the kidney and urinary tract, CAKUT, of mice and men. Mol Cell 1999; 3: 1–10[ISI][Medline]
  12. Ozono R, Wang ZQ, Moore AF, Inagami T, Siragy HM, Carey RM. Expression of the subtype-2 angiotensin (AT2) receptor protein in rat kidney. Hypertension 1997; 30: 1238–1246[Abstract/Free Full Text]
  13. Goto M, Mukoyama M, Suga S et al. Growth-dependent induction of angiotensin II type 2 receptor in rat mesangial cells. Hypertension 1997; 30: 358–362[Abstract/Free Full Text]
  14. Zhuo J, Dean R, MacGregor D, Alcorn D, Mendelsohn FAO. Presence of angiotensin II AT2 receptor binding sites in the adventitia of human kidney vasculature. Clin Exp Pharmacol Physiol 1996; [Suppl. 3]: S147–154
  15. Siragy HM, Carey RM. The subtype 2 angiotensin receptor regulates renal prostaglandin F2{alpha} formation in conscious rats. Am J Physiol 1997; 273: R1103–1107[Abstract/Free Full Text]
  16. Lo M, Liu KL, Lantelme P, Sassard J. Subtype 2 of angiotensin II receptors controls pressure-natriuresis in rats. J Clin Invest 1995; 95: 1394–1397[ISI][Medline]
  17. Haithcock D, Jiao H, Cui XL, Hopfer U, Douglas JG. Renal proximal tubular AT, receptor: Signaling and transport. J Am Soc Nephrol 1999; 10: S69–74[ISI][Medline]
  18. Endo Y, Arima S, Yaoita H et al. Function of angiotensin II type 2 receptor in the postglomerular efferent arteriole. Kidney Int 1997; 52 [Suppl. 53]: S205–207
  19. Thorup C, Kornfeld M, Goligorsky MS, Moore LC. AT1 receptor inhibition blunts angiotensin II-stimulated nitric oxide release in renal arteries. J Am Soc Nephrol 1999; 10: S220–224[ISI][Medline]
  20. Mundel P, Bachmann S, Bader M et al. Expression of nitric oxide synthase in kidney macula densa cells. Kidney Int 1992; 42: 1017–1019[ISI][Medline]
  21. Wilcox CS, Welch WJ, Murad F et al. Nitric oxide synthase in macula densa regulates glomerular capillary pressure. Proc Natl Acad Sci USA 1992; 89: 11993–11997[Abstract]
  22. Ma J, Nishimura H, Fogo A, Kon V, Inagami T, Ichikawa I. Accelerated fibrosis and collagen deposition develop in the renal interstitium of angiotensin type 2 receptor null mutant mice during ureteral obstruction. Kidney Int 1998; 53: 937–944[ISI][Medline]
  23. Siragy HM, Carey RM. Protective role of the angiotensin AT2 receptor in a renal wrap hypertension model. Hypertension 1999; 33: 1237–1242[Abstract/Free Full Text]
  24. Siragy HM, Senbonmatsu T, Ichiki T, Inagami T, Carey M. Increased renal vasodilator prostanoids prevent hypertension in mice lacking the angiotensin subtype-2 receptor. J Clin Invest 1999; 104: 181–188[Abstract/Free Full Text]
  25. Endo Y, Arima S, Yaoita H, Tsunoda K, Omata K, Ito S. Vasodilation mediated by angiotensin II type 2 receptor is impaired in afferent arterioles of young spontaneously hypertensive rats. J Vasc Res 1998; 35: 421–427[ISI][Medline]
  26. Christen Y, Waeber B, Nussberger J et al. Oral administration of Dup 753, a specific angiotensin II receptor antagonist, to normal male volunteers. Inhibition of pressor response to exogenous angiotensin I and II. Circulation 1991; 83: 1333–1342[Abstract]