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

Abstract

378T he development and progression of hypertension differs between men and women. Before menopause, arterial pressure is lower in women than in men of similar age. 1 However, after menopause, this cardioprotection in women is lost, and a higher proportion of women than men have hypertension after the age of 65 years.1 Similar differences in arterial pressure control have been observed in other mammalian species, including spontaneously hypertensive rats (SHRs). 2,3These sex-related differences in the development of hypertension have been strongly linked to sexual dimorphism in the renin-angiotensin system (RAS), which plays a pivotal role in the long-term regulation of arterial pressure. 3,4 Classically, angiotensin II (AngII) acts via the angiotensin type 1 receptor (AT 1 R) to cause vasoconstriction and sodium retention. Activation of the pressor RAS is a key mediator in the development of hypertension, and drugs that target this system are mainstays of current antihypertensive therapy. More recently, a depressor arm of the RAS has been recognized, which counterbalances the actions of AngII at AT 1 R. AngII together with other biologically active angiotensin peptides, including angiotensin (1-7) and angiotensin III, interact with angiotensin type 2 receptor (AT 2 R) to evoke vasodilatation and natriuresis. Overwhelming evidence suggests that the depressor RAS is upregulated in women by estrogen, and this contributes to sexual dimorphism in arterial pressure control.3,4 It is, therefore, plausible that enhancement of the depressor RAS, and in particular the AT 2 R, may represent a novel therapeutic target in the treatment of hypertension, particularly in women.Our recent data from normotensive rats support the notion that AT 2 R plays an integral, yet sexually dimorphic, functional Abstract-Accumulating evidence suggests that the protective pathways of the renin-angiotensin system are enhanced in women, including the angiotensin type 2 receptor (AT 2 R), which mediates vasodilatory and natriuretic effects. To provide insight into the sex-specific ability of pharmacological AT 2 R stimulation to modulate renal function in hypertension, we examined the influence of the AT 2 R agonist, compound 21 (100-300 ng/kg per minute), on renal function in 18-to 19-weekold anesthetized male and female spontaneously hypertensive rats. AT 2 R stimulation significantly increased renal blood flow in female hypertensive rats (P Treatment <0.001), without influencing arterial pressure. For example, at 300 ng/kg per minute of compound 21, renal blood flow increased by 14.3±1.8% from baseline. Furthermore, at 300 ng/kg per minute of compound 21, a significant increase in urinary sodium excretion was observed in female hypertensive rats (+180±59% from baseline; P<0.05 versus vehicle-treated rats). This was seen in the absence of any major change in glomerular filtration rate, indicating that the natriuretic effects of AT 2 R stimulation were likely the result of altered renal tubular function. Conversely, we did not observe any sign...

Prevention of diabetic nephropathy by compound 21, selective agonist of angiotensin type 2 receptors, in Zucker diabetic fatty rats

“…AT 2 receptors are expressed to a greater extent in the kidney of female SHR rats, suggesting sexspecific effects of AT 2 stimulation by C21 on the kidney (10). In this regard, we can speculate that the effects of C21 in the prevention of diabetic nephropathy, which we are showing here in male ZDF rats, could be similar or even larger in female rats.…”

“…In stroke-prone spontaneously hypertensive rats, C21 improved endothelium-dependent relaxation in mesenteric arteries in combination with an AT 1 antagonist (24). Acute administration of C21 induced vasodepressor effects in spontaneously hypertensive rats (SHR) (5) and increased renal blood flow in female SHR, but not in male SHR (10). In SHR, but not in WistarKyoto rats, a C21-dependent renal vasodilator effect, un-masked by angiotensin-converting enzyme inhibition, is mediated by nitric oxide (6).…”

RAS and sex differences in diabetic nephropathy

“…Acute C21 administration improved renal function in female, but not in male, spontaneously hypertensive (SHR) rats. Considering that AT 2 R are expressed to a greater extent in the kidney of female SHR rats (44), this effect of C21 in DN prevention seems to be more effective in female rats than in males.…”

Renin-angiotensin-aldosterone system and the aging kidney

“…Finally, extensive evidence suggests that the protective pathways of the RAAS are enhanced in young women, including the angiotensin type 2 receptor, which mediates vasodilatory and natriuretic effects. In this sense, recent studies in animal models have documented that acute angiotensin type 2 receptor stimulation enhanced renal vasodilatation and sodium excretion without concomitant alterations in the glomerular filtration rate in female hypertensive rats [13].…”