Sex-specific influence of angiotensin type 2 receptor stimulation on renal function: a novel therapeutic target for hypertension

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: 13.1±2.4% versus females: 23.0±3.2% change in renal blood flow at 300 ng/kg per minute versus baseline; P<0.01). In addition, AT(2)R stimulation significantly increased sodium and water excretion to a similar extent in males and females (P(Group)=0.05 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.