Impact of the direct angiotensin II type 2 receptor stimulation on renal function toward a sex-specific therapeutic approach for hypertension.

H ypertension and cardiovascular diseases are more prevalent in men than in premenopausal women of the same age. However, after menopause, this cardiovascular protection in women is lost, possibly because of the unbalance of estro-gen production and other sex hormones in postmenopause. Although the mechanisms underlying these sex differences remain unclear, divergences in the function of the renin-angiotensin system (RAS) and differences in the response to stimulation and inhibition of RAS in men and premenopausal women have been proposed. 1,2 RAS is involved in blood pressure regulation by modulating vascular tone and renal excretory function. In particular, the kidney is involved in the long-term regulation of arterial pressure by modulating sodium excretion. 1 It is now generally accepted that RAS organization is dual and that beside the well-known main pressor axis (angio-tensin-converting enzyme/angiotensin [Ang] II/Ang type 1 receptor [AT1R]), there is a second depressor protective axis consisting of Ang type 2 receptor (AT2R), angiotensin-converting enzyme 2, Ang-(1–7), and MasR. 1 In particular, AT2R mediates the vasodilatory and natriuretic actions of angioten-sin peptides. AT2R is expressed throughout the kidney in both vascular and tubular elements, and it is greatly expressed in renal proximal tubule cells. 1,2 AT2R induces vasodilation in both resistance and capacitance vessels, protects the kidney from AT1R-mediated inflammation and ischemic damage, and may contribute to the beneficial natriuretic response to angio-tensin receptor blockers. 1 In humans and animal models, sex differences exist in the regulation of arterial pressure and renal function by RAS, possibly through a different balance in the pressor and depres-sor arms of the system. Accumulating evidence suggests that vasodepressor RAS pathways are enhanced in women and that AT2R plays a prominent role in arterial pressure regulation in premenopausal women. 2 In normotensive and hypertensive mice and rats, AT2R expression is enhanced in the vasculature of females, 2 particularly in the kidney. It has been shown that AT2R is expressed to a greater extent in the kidney and vas-culature of female rats and mice. 2,3 Therefore, AT2R seems to play a role in opposing the pressor actions induced by AT1R stimulation in females via an estrogen-dependent mechanism and may contribute to sex differences in arterial pressure control, causing vasodilation and decreased renal sodium reabsorption. 4 AT2R attenuates the Ang II–dependent resetting of tubu-loglomerular feedback, which contributes to setting pressure-natriuresis properties. This effect is not evident in male mice and underlines the protective role of the AT2R …