Sex-Specific Influence of Angiotensin Type 2 Receptor Stimulation on Renal Function

Abstract

Abstract-The renin-angiotensin system is a powerful regulator of arterial pressure and body fluid volume. Increasing evidence suggests that the angiotensin type 2 receptor (AT 2 R), which mediates the vasodilatory and natriuretic actions of angiotensin peptides, is enhanced in females and may, therefore, represent an innovative therapeutic target. We investigated the therapeutic potential of direct AT 2 R stimulation on renal function in 11-to 12-week-old anesthetized male and female Sprague-Dawley rats. Renal blood flow was examined in response to a graded infusion of the highly selective, nonpeptide AT 2 R agonist, compound 21 (100, 200, and 300 ng/kg per minute), in the presence and absence of AT 2 R blockade (PD123319; 1 mg/kg per hour). Direct AT 2 R stimulation significantly increased renal blood flow in both males and females, without influencing arterial pressure. This was dose dependent in females only and occurred to a greater extent in females at the highest dose of compound 21 administered (males: 13.1Ϯ2.4% versus females: 23.0Ϯ3.2% change in renal blood flow at 300 ng/kg per minute versus baseline; PϽ0.01). In addition, AT 2 R stimulation significantly increased sodium and water excretion to a similar extent in males and females (P Group ϭ0.05 and 0.005). However, there was no significant change in glomerular filtration rate in either sex, suggesting that altered tubular function may be responsible for AT 2 R-induced natriuresis rather than hemodynamic effects. Taken together, this study provides evidence that direct AT 2 R stimulation produces vasodilatory and natriuretic effects in the male and female kidney. The AT 2 R may, therefore, represent a valuable therapeutic target for the treatment of renal and cardiovascular diseases in both men and women. Key Words: angiotensin type 2 receptor Ⅲ compound 21 Ⅲ sex differences Ⅲ hypertension Ⅲ natriuresis Ⅲ renal blood flow B efore menopause, women are protected from hypertension and cardiovascular disease relative to men. However, this protection weakens after menopause, and ultimately the prevalence of hypertension in women exceeds that of men. 1 Alarmingly, sex-related differences have also been reported in the efficacy of current cardiovascular therapies, 2,3 with poorer treatment outcomes commonly reported in women. 3 The development of sex-specific approaches for the treatment of hypertension and cardiovascular disease is, therefore, of utmost importance.It is well established that the kidney plays a central role in arterial pressure control. The regulation of sodium excretion by the kidney is critical to the long-term regulation of arterial pressure given its influence on body fluid volume homeostasis. 4 In response to a rise in arterial pressure, sodium and water excretion is increased to reduce extracellular fluid volume and to restore arterial pressure to normal. Abnormal renal excretory function is, therefore, recognized as a key contributor to the development of hypertension. 5The renin-angiotensin system (RAS) plays a pivotal role in the re...

Angiotensin Type 2 Receptor Stimulation Increases Renal Function in Female, but Not Male, Spontaneously Hypertensive Rats

“…7 This observation of a sex-specific renal vascular response to C21 in the present study is consistent with our previous observations in rodents that AT 2 R plays a greater functional role in female than in male renal vasculature, providing protection against the vasoconstrictor effects of AngII. 5,6,8 Furthermore, our data support the notion that differences in the renal response to C21 between male and female SHRs is attributable to sex differences in renal AT 2 R expression. We observed significantly greater basal AT 2 R mRNA expression in the kidneys of female SHRs as compared with male SHRs, in agreement with the previous findings of Silva-Antonialli et al 2 In addition, although we observed significantly greater renal angiotensin type 1a receptor expression in female SHRs as compared with their male counterparts, the relative AT 2 R-to-AT 1 R ratio was much greater in female than in male SHRs, although such sex differences in basal renal AT 1 R or AT 2 R mRNA expression are not always reported.…”

“…This finding is somewhat surprising given that we and others have previously reported significant natriuretic effects of AT 2 R stimulation alone in numerous male rodent models, including normotensive Sprague-Dawley rats, uninephrectomized rats, and obese Zucker rats. 6,[13][14][15] This finding suggests that the lesser renal AT 2 R expression we and others have identified in male versus female SHRs may be responsible for the lack of natriuretic response of male SHRs to C21 in the present study.…”

“…This ability of C21 to increase RBF in the absence of any major change in GFR is similar to what we observed previously in male and female normotensive rats. 6 As discussed in this previous study, there are several possible mechanisms that could explain no change in GFR while RBF increased. First, similar vasodilatory effects of C21 at the pre-and postglomerular vessels occurred such that RBF can increase in the absence of any change in GFR.…”

“…In addition, we recently demonstrated that acute administration of the selective AT 2 R agonist, compound 21 (C21), produced significant vasodilatory and natriuretic effects in the kidney of both female and male normotensive rats. 6 The ability of C21 to induce natriuresis was similar between the sexes; however, C21 induced a greater increase in RBF in female rats. Remarkably, these effects were observed in the absence of any AT 1 R blockade, demonstrating the ability of C21 to directly modulate renal function in male and female normotensive rats.…”

“…Remarkably, these effects were observed in the absence of any AT 1 R blockade, demonstrating the ability of C21 to directly modulate renal function in male and female normotensive rats. 6 Despite this evidence for a significant functional role of AT 2 R in the kidney in male and female normotensives, the sex-specific ability of pharmacological AT 2 R stimulation to modulate renal function in hypertension remains unknown. Therefore, we aimed to provide further insight into the ability of pharmacological AT 2 R stimulation using C21 to modulate renal hemodynamic and excretory function in hypertension using the SHR model.…”