Sex differences in the intrarenal renin angiotensin system during angiotensin II-dependent hypertension and salt loading
Description
Males have greater hypertension prevalence and progression than females suggesting sex differences in the underlying mechanisms. This study investigates the intrarenal renin-angiotensin system (RAS) to resolve the hypothesis that sexual dimorphism in the responses of intrarenal angiotensinogen (AGT) and renin synthesized in the collecting ducts (CD renin) exacerbate hypertension in male more than female Sprague-Dawley rats during chronic Angiotensin II infusion (Ang II) (80 ng/min). Additionally, high salt (HS) diet (8% NaCl) was administered to assess sex differences in these RAS components response. Measurements of AGT and CD renin gene expression and urinary excretion showed that AGT message levels were higher in normal salt (NS), HS and Ang II males than females. CD renin expression is lower in female than male rats and responds to HS by increasing in females but is unchanged in the males. Urinary renin excretion is lower in all females than males. Urinary Ang II (uAng II) levels are lower in females than males fed NS or HS diet. Therefore a basal sex difference exists whereby males have higher levels of intrarenal AGT and CD renin. Female rats with Ang II infusion have greater uAngII levels than the Ang II males and the addition of HS diet exacerbates the uAngII levels of males but not female rats. SBP also showed salt sensitivity in Ang II male rats but not females. An Ang II receptor blocker (ARB) was administered to assess sex differences in RAS therapy and the effects of estrogen on AGT and CD renin were assessed in a cohort of ovariectomized (OVX) females. ARB treatments returned SBP to normal in both sexes, but only in females were the proteinuria and increased uAGT prevented. CD renin message and excretion levels were decreased in Ang II OVX rats vs. intact and uAngII was also reduced suggesting that the loss of estrogen did not exacerbate the intrarenal RAS. In summary, decreased levels of AGT and CD renin in female rats suggests a less active intrarenal RAS than in males. Exacerbation of uAGT, proteinuria and uAng II in males by HS diet during Ang II infusion demonstrates augmented salt sensitivity compared to females which would increase the progression of hypertension