Sex Differences in the Pressor and Tubuloglomerular Feedback Response to Angiotensin II

Abstract

Abstract-Awareness of sex differences in the pathology of cardiovascular disease is increasing. Previously, we have shown a role for the angiotensin type 2 receptor (AT 2 R) in the sex differences in the arterial pressure response to Ang II. Tubuloglomerular feedback (TGF) contributes in setting pressure-natriuresis properties, and its responsiveness is closely coupled to renal Ang II levels. We hypothesize that, in females, the attenuated pressor response to Ang II is mediated via an enhanced AT 2 R mechanism that, in part, offsets Ang II-induced sensitization of the TGF mechanism. Mean arterial pressure was measured via telemetry in male and female wild-type (WT) and AT 2 R knockout (AT 2 R-KO) mice receiving Ang II (600 ng/kg per minute SC). Basal 24-hour mean arterial pressure did not differ among the 4 groups. After 10 days of Ang II infusion, mean arterial pressure increased in the male WT (28Ϯ6 mm Hg), male AT 2 R-KO (26Ϯ2 mm Hg), and female AT 2 R-KO (26Ϯ4 mm Hg) mice, however, the response was attenuated in female WT mice (12Ϯ4 mm Hg; P between sex and genotypeϭ0.016). TGF characteristics were determined before and during acute subpressor Ang II infusion (100 ng/kg per minute IV). Basal TGF responses did not differ between groups. The expected increase in maximal change in stop-flow pressure and enhancement of TGF sensitivity in response to Ang II was observed in the male WT, male AT 2 R-KO, and female AT 2 R-KO but not in the female WT mice (P between sex and genotype Ͻ0.05; both). In conclusion, these data indicate that an enhanced AT 2 R-mediated pathway counterbalances the hypertensive effects of Ang II and attenuates the Ang II-dependent resetting of TGF activity in females. Thus, the enhancement of the AT 2 R may, in part, underlie the protection that premenopausal women demonstrate against cardiovascular disease. Key Words: sex differences Ⅲ renin-angiotensin system Ⅲ Ang II Ⅲ mean arterial pressure Ⅲ hypertension Ⅲ renal hemodynamics Ⅲ tubuloglomerular feedback M en have a greater prevalence for hypertension and cardiovascular disease than premenopausal women of the same age. 1 The mechanisms underlying these differences in the pathophysiology of cardiovascular disease between men and women remain unclear. One of the suggested mechanisms underlying this sexual dimorphism is differences in the function of the renin-angiotensin system (RAS). [2][3][4] Angiotensin II (Ang II), the main effector peptide of the RAS, exerts its effects through 2 main receptor subtypes. Stimulation of the angiotensin type 1 receptor (AT 1 R) causes vasoconstriction, sodium reabsorption, and cell proliferation. The angiotensin type 2 receptor (AT 2 R) opposes the AT 1 R, causing vasodilation, sodium excretion, and apoptosis. 5,6 Earlier studies have shown that females have a greater AT 2 R:AT 1 R ratio. 7,8 We, and others, have demonstrated previously that the rise in arterial pressure in response to Ang II is blunted in females compared with males. 7,9 -11 Furthermore, we have provided evidence to suggest that arteria...

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.…”

Sex-Related Differences in Hypertension

“…35,36 More recently, we extended these findings to AT 2 R-knockout mice, demonstrating that the chronic pressor response to Ang II was attenuated in female wild-type mice compared with male wild-type and female AT 2 R-knockout mice. 37 These findings illustrate the dual nature of Ang II on arterial pressure control 38 and support an enhanced role for AT 2 R in regulating arterial pressure in females.…”

“…42 The sensitivity of the tubuloglomerular feedback mechanism, which is an important regulator of glomerular filtration rate, to Ang II is also reduced by the presence of AT 2 R in female, but not male, mice. 37 Finally, we have also provided evidence that direct AT 2 R stimulation, with the AT 2 R agonist Compound 21, produces renal vasodilatation and natriuresis in male and female normotensive rats. AT 2 R may, therefore, represent a valuable therapeutic target for the treatment of renal disease and CVDs in both men and women.…”

Newly Discovered Components and Actions of the Renin–Angiotensin System

“…1 Several recent studies have demonstrated sex differences in the renal responses to AT 2 R activation, wherein greater renal vasodilation could be demonstrated in the female as compared with male rats. [34][35][36] Indeed, the ratio of AT 2 R:AT 1 R expression in the renal vasculature is greater in females than in males. 34 However, sex differences were not apparent at the level of renal tubule Na + and fluid reabsorption.…”

“…[34][35][36] Indeed, the ratio of AT 2 R:AT 1 R expression in the renal vasculature is greater in females than in males. 34 However, sex differences were not apparent at the level of renal tubule Na + and fluid reabsorption. 36,37 Thus, some but not all of the actions of AT 2 Rs are sex dependent.…”