The renin-angiotensin system (RAS) is a coordinated hormonal cascade in the control of cardiovascular, renal, and adrenal function that governs body fluid and electrolyte balance, as well as arterial pressure. The classical RAS consists of a circulating endocrine system in which the principal effector hormone is angiotensin (ANG) II. ANG is produced by the action of renin on angiotensinogen to form ANG I and its subsequent conversion to the biologically active octapeptide by ANG-converting enzyme. ANG II actions are mediated via the ANG type 1 receptor. Here, we discuss recent advances in our understanding of the components and actions of the RAS, including local tissue RASs, a renin receptor, ANG-converting enzyme-2, ANG (1-7), the function of the ANG type 2 receptor, and ANG receptor heterodimerization. The role of the RAS in the regulation of cardiovascular and renal function is reviewed and discussed in light of these newly recognized components.

The angiotensin AT 2 receptor modulates renal production of cyclic guanosine 3 Ј , 5 Ј -monophosphate (cGMP; J. Clin. Invest. 1996Invest. . 97:1978Invest. -1982. In the present study, we hypothesized that angiotensin II (Ang II) acts at the AT 2 receptor to stimulate renal production of nitric oxide leading to the previously observed increase in cGMP. Using a microdialysis technique, we monitored changes in renal interstitial fluid (RIF) cGMP in response to intravenous infusion of the AT 2 receptor antagonist PD 123319 (PD), the AT 1 receptor antagonist Losartan, the nitric oxide synthase (NOS) inhibitor nitro-L -arginine-methyl-ester ( L -NAME), the specific neural NOS inhibitor 7-nitroindazole (7-NI), or Ang II individually or combined in conscious rats during low or normal sodium balance.Sodium depletion significantly increased RIF cGMP. During sodium depletion, both PD and L -NAME caused a similar decrease in RIF cGMP. Combined administration of PD and L -NAME decreased RIF cGMP to levels observed with PD or L -NAME alone or during normal sodium intake.During normal sodium intake, Ang II caused a twofold increase in RIF cGMP. Neither PD nor L -NAME, individually or combined, changed RIF cGMP. Combined administration of Ang II and either PD or L -NAME produced a significant decrease in RIF cGMP compared with that induced by Ang II alone. Combined administration of Ang II, PD, and L -NAME blocked the increase in RIF cGMP produced by Ang II alone.During sodium depletion, 7-NI decreased RIF cGMP, but the reduction of cGMP in response to PD alone or PD combined with 7-NI was greater than with 7-NI alone. During normal sodium intake, 7-NI blocked the Ang II-induced increase in RIF cGMP. PD alone or combined with 7-NI produced a greater inhibition of cGMP than did 7-NI alone. During sodium depletion, 7-NI (partially) and L -NAME (completely) inhibited RIF cGMP responses to L -arginine.These data demonstrate that activation of the reninangiotensin system during sodium depletion increases renal nitric oxide production through stimulation by Ang II at the angiotensin AT 2 receptor. This response is partially mediated by neural NOS, but other NOS isoforms also contribute to nitric oxide production by this pathway. (

In situ hybridization studies have suggested that the subtype 2 angiotensin (AT2) receptor gene is expressed in fetal and newborn rat kidney but is undetectable in the adult animals. In the present study, we investigated the expression of AT2 receptor protein in the fetal (days 14 and 19 of fetal life), newborn (day 1 postpartum), and adult (4-week-old and 3-month-old) rat kidney. Polyclonal anti-peptide antiserum was raised against the amino terminus of the native AT2 receptor. The selectivity of the antiserum was validated by recognition of the AT2 receptor in a stably transfected COS-7 cell line by Western blot and immunocytochemical analysis. As a positive control, the AT2 receptor signal was detected strongly in the adrenal gland. Positive immunohistochemical staining was observed in the mesenchymal cells and ureteric buds of the 14-day fetal kidney and in the glomeruli, tubules, and vessels in the 19-day fetal and newborn kidney. Glomeruli expressing the AT2 receptor were localized mainly in the outer layer of the renal cortex. In the young (4-week-old) and mature (3-month-old) adult rat on normal sodium intake, renal AT2 receptor immunoreactivity was present in glomeruli but substantially diminished compared with that of newborn rats. In both young and mature adult rats, dietary sodium depletion increased the renal AT2 receptor signal, mainly in the glomeruli and interstitial cells. Preimmune and preadsorption controls were negative. Western blot analysis detected a single 44-kD band in the fetal and newborn rat kidney and in the young and mature adult rat kidney. Dietary sodium depletion increased the density of the AT2 receptor band in mature adult rat kidneys. These data provide evidence that the AT2 receptor protein is expressed in the fetal and newborn rat kidney, diminishes in adult life, and is reexpressed in the adult in response to sodium depletion.

The renal effects of angiotensin II(AII) are attributed to AT 1 receptors. In contrast, the function of renal AT 2 receptors is unknown. Using a microdialysis technique, we monitored changes in renal interstitial fluid (RIF) prostaglandin E 2 (PGE 2 ) and cyclic guanosine 3 Ј , 5 Ј -monophosphate (cGMP) in response to dietary sodium (Na) depletion alone, or Na depletion or normal Na diet combined with the AT 1 receptor blocker, Losartan, the AT 2 receptor blocker, PD 123319 (PD), or angiotensin II, individually or combined in conscious rats. Na depletion significantly increased PGE 2 and cGMP. During Na depletion, Losartan decreased PGE 2 and did not change cGMP. In contrast, PD significantly increased PGE 2 and decreased cGMP. Combined administration of Losartan and PD decreased PGE 2 and cGMP.During normal Na diet, RIF PGE 2 and cGMP increased in response to angiotensin II. Neither Losartan nor PD, individually or combined, changed RIF PGE 2 or cGMP. Combined administration of angiotensin II and Losartan or PD produced a significant decrease in response of PGE 2 and cGMP to angiotensin II, respectively.

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 (AT 1 ) ANG receptor. Until recently, the functional role of the type 2 (AT 2 ) receptor, if any, has been unknown, possibly because the AT 2 receptor has a low degree of expression compared with that of the AT 1 receptor. Evidence has now accumulated that the AT 2 receptor opposes functions mediated by the AT 1 receptor. Whereas the AT 1 receptor stimulates cell proliferation, the AT 2 receptor inhibits proliferation and promotes cell differentiation. These differences in growth responses have been ascribed to different cell signaling pathways in which the AT 1 receptor stimulates protein phosphorylation and the AT 2 receptor dephosphorylation. During the past 5 years, studies have demonstrated that the AT 2 receptor is responsible for vasodilation and natriuresis, thus opposing the vasoconstrictor and antinatriuretic effects of ANG II mediated through the AT 1 receptor. Work from our laboratory and others indicates that the AT 2 receptor stimulates vasodilation and natriuresis by an autocrine cascade including bradykinin, nitric oxide, and cyclic GMP. The AT 2 receptor also has been found to control vasodilator prostaglandins, which have a role in blood pressure regulation. The AT 2 receptor appears to play a counterregulatory protective role in the regulation of blood pressure and sodium excretion that opposes the AT 1 receptor. Key Words: angiotensin II Ⅲ receptors, angiotensin II Ⅲ blood pressure Ⅲ kidney Ⅲ sodium T he renin-angiotensin system is a major physiological regulator of body fluid volume, electrolyte balance, and blood pressure. 1-4 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, AT 1 and AT 2 . 1-6 AT 1 receptors were defined as those selectively blocked by biphenylimidazoles such as losartan, whereas AT 2 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 AT 1 receptor, and the functions of the AT 2 receptor were unknown. [1][2][3][4] More recently, each of these receptors has been cloned and the signal transduction mechanisms for the AT 1 and AT 2 receptors have been clarified. [1][2][3][4]7,8 We now have available a great deal of information concerning the recepto...

The vast majority of the known biological effects of the renin-angiotensin system are mediated by the type-1 (AT 1 ) receptor, and the functions of the type-2 (AT 2 ) receptor are largely unknown. We investigated the role of the AT 2 receptor in the vascular and renal responses to physiological increases in angiotensin II (ANG II) in mice with targeted deletion of the AT 2 receptor gene. Mice lacking the AT 2 receptor (AT 2 -null mice) had slightly elevated systolic blood pressure (SBP) compared with that of wild-type (WT) control mice (P < 0.0001). In AT 2 -null mice, infusion of ANG II (4 pmol͞kg͞min) for 7 days produced a marked and sustained increase in SBP [from 116 ؎ 0.5 to 208 ؎ 1 mmHg (P < 0.0001) (1 mmHg ‫؍‬ 133 Pa)] and reduction in urinary sodium excretion (U Na V) [from 0.6 ؎ 0.01 to 0.05 ؎ 0.002 mM͞day (P < 0.0001)] whereas neither SBP nor U Na V changed in WT mice. AT 2 -null mice had low basal levels of renal interstitial f luid bradykinin (BK), and cyclic guanosine 3,5-monophosphate, an index of nitric oxide production, compared with WT mice. In WT mice, dietary sodium restriction or ANG II infusion increased renal interstitial f luid BK, and cyclic guanosine 3,5-monophosphate by Ϸ4-fold (P < 0.0001) whereas no changes were observed in AT 2 -null mice. These results demonstrate that the AT 2 receptor is necessary for normal physiological responses of BK and nitric oxide to ANG II. Absence of the AT 2 receptor leads to vascular and renal hypersensitivity to ANG II, including sustained antinatriuresis and hypertension. These results strongly suggest that the AT 2 receptor plays a counterregulatory protective role mediated via BK and nitric oxide against the antinatriuretic and pressor actions of ANG II.The renin-angiotensin system is a major hormonal cascade regulating body fluid volume, electrolyte balance, and arterial pressure (1, 2). Angiotensin II (ANG II), the principle effector peptide, acts by binding to its two isoform receptors, AT 1 and AT 2 . The vast majority of the known vascular and renal actions of ANG II are thought to be mediated via the AT 1 receptor (1, 2). However, it has been demonstrated in the rat that ANG II acts at the renal AT 2 receptor to stimulate bradykinin (BK) and, via a nitric oxide mediated pathway, cyclic guanosine 3Ј, 5Ј-monophosphate (cGMP) production (3, 4, 5). Gohlke et al. (6) also recently showed in the rat that AT 2 receptor stimulation increased aortic cGMP by increasing BK and NO formation.Disruption of the AT 2 receptor has been reported (7, 8). Mice lacking the AT 2 receptor develop normally but have reduced exploratory behavior, impaired drinking responses to water deprivation, normal or slightly increased baseline blood pressure, and an exaggerated acute pressor response to a pharmacological injection of ANG II. These results, together with previous studies, suggested that the AT 2 receptor may play a protective role in blood pressure regulation.We conducted the present study to investigate the role of the AT 2 receptor in the acute and chr...

Abstract-We evaluated the role of the renal angiotensin II type 2 (AT 2 ) receptor in blood pressure regulation in rats with 2-kidney, 1 figure-8 wrap (Grollman) hypertension. Renal wrapping increased systolic blood pressure (SBP). Renal interstitial fluid (RIF) bradykinin (BK), nitric oxide end-products (NOX), and cGMP were higher in the contralateral intact kidney than in the wrapped kidney. In rats with Grollman hypertension, losartan normalized SBP and increased renal function, RIF BK, NOX, and cGMP only in contralateral kidneys. In contrast, PD 123319, a specific AT 2 -receptor antagonist, significantly increased SBP and decreased RIF BK, NOX, and cGMP in both kidneys. Combined administration of losartan and PD 123319 prevented the decrease in SBP and the increase in RIF BK, NOX, and cGMP levels observed with losartan alone. BK-receptor blockade caused a significant increase in RIF BK and a decrease in RIF NOX and cGMP in both kidneys similar to that observed during administration of PD 123319. In rats that underwent sham operation, RIF BK increased in response to angiotensin II, an effect that was blocked by PD 123319. These data demonstrate that angiotensin II mediates renal production of BK, which, in turn, releases nitric oxide and cGMP via stimulation of AT 2 receptors. The increase in blood pressure and the decrease in renal BK, nitric oxide, and cGMP during AT 2 -receptor blockade suggests that the AT 2 receptor mediates counterregulatory vasodilation in Grollman hypertension and prevents a further increase in blood pressure. (Hypertension. 1999;33:1237-1242.)Key Words: receptors, angiotensin II Ⅲ hypertension, renovascular Ⅲ bradykinin Ⅲ cyclic GMP Ⅲ angiotensin II A ngiotensin (Ang) II is established as an important factor in the pathophysiology of renal vascular hypertension. The majority of studies suggest that the renal actions of Ang II are mediated by angiotensin subtype AT 1 receptors. 1 However, AT 2 receptors also are present in the kidney. 2 The physiological actions of Ang II at the AT 2 receptor have been difficult to determine, at least in part, because AT 2 receptors have a low degree of expression compared with AT 1 receptors. 3 We recently demonstrated that AT 2 receptors mediate cGMP 4 through generation of renal nitric oxide. 5 In the present study, we used a hypertensive rat model 6,7 to investigate the role of the AT 2 receptor in blood pressure regulation. We studied conscious rats with 2-kidney, 1 figure-8 wrap (Grollman) hypertension during normal sodium intake and rats that underwent sham operation and were treated with Ang II. This study was conducted to examine the hypothesis that in Ang II-dependent hypertension, the AT 2 receptor subserves a protective role in blood pressure regulation mediated by AT 2 -receptor augmentation of renal bradykinin (BK), nitric oxide, and cGMP production. Methods Renal Microdialysis TechniqueTo determine the levels of renal interstitial fluid (RIF) BK, nitric oxide end-products (NOX), cGMP, and Ang II, we constructed a microdialysis probe as ...

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