370 SEX-SPECIFIC ROLE OF THE ANGIOTENSIN TYPE 2 RECEPTOR in the renal vasculature

Abstract

Recently, a depressor axis of the renin-angiotensin system (RAS) has been discovered allowing us to widen our search for anti-hypertensive targets beyond the classical RAS. Moreover, accumulating evidence suggests that the vasodepressor RAS pathways are enhanced in females, including the angiotensin type 2 receptor (AT2R), which mediates vasodilatory and natriuretic effects. A major focus of our recent work has been to explore the sex-specific renoprotective effects of AT2R stimulation to establish whether the AT2R may be a suitable therapeutic target, particularly in females. We have examined the acute renal haemodynamic and excretory response to direct AT2R stimulation in male and female anaesthetised normotensive rats using a range of highly selective AT2R agonists, including the non-peptide agonist, Compound 21, and the recently developed β-substituted angiotensin III peptidomimetic, β-Pro-AngIII. In both sexes, direct AT2R stimulation significantly increased renal blood flow in the absence of any change in arterial pressure. These responses occurred to a greater extent in females, suggesting that the AT2R plays a sex-specific role in the renal vasculature. Nonetheless, direct AT2R stimulation has the ability to modulate renal vasodilatory function in both sexes. In addition, sodium and water excretion increased to a similar extent in males and females. So far, these investigations have provided significant evidence that direct AT2R stimulation offers renoprotection through its vasodilatory and natriuretic effects in the kidney, and this role is enhanced in females. It is now a matter for future investigations to establish whether selective AT2R agonists offer therapeutic potential in the setting of hypertension.