Gender Differences in the Renal Response to Renin-Angiotensin System Blockade

Abstract

Evidence suggests that gender differences exist in renin-angiotensin system (RAS) function. It was hypothesized that women may differ also in their response to RAS blockade. The renal and peripheral hemodynamic responses to incremental dosages of an angiotensin receptor blocker and the degree of angiotensin II (AngII) insensitivity achieved during 8 wk were examined in men and women. Participants were 30 young healthy men (n ‫؍‬ 15; mean age 27 ؎ 2) and women (n ‫؍‬ 15; mean age 28 ؎ 2) who were on a controlled sodium and protein diet for 1 wk before each study. The humoral, renal, and systemic response to incremental dosages of irbesartan (75 mg for 4 wk, then 150 mg for 4 wk) was assessed, as was the pressor response to AngII (3 ng/kg per min), at 2-wk intervals. AngII type 1 receptor expression in skin biopsies was assessed at baseline and after 8 wk by a real-time PCR protocol. Men and women both exhibited significant declines in BP. Women achieved significantly reduced AngII sensitivity compared with men at lower dosages, showing no pressor response at 4 wk of 75 mg/d irbesartan, whereas men continued to exhibit a pressor response at 4 wk of 150 mg/d. Receptor expression at baseline did not differ between men and women but by 8 wk was significantly decreased in women and unchanged in men. Our findings indicate that men may require larger dosages of angiotensin receptor blocker than do women and that the BP response cannot be used as a surrogate marker for adequate RAS blockade of the renal microvasculature.J Am Soc Nephrol 17: 2554 -2560 , 2006 . doi: 10.1681 C linical and epidemiologic evidence suggests that women with renal disease progress more slowly to end stage in comparison with men (1). The mechanisms underlying this difference remain unknown, but evidence indicates that at least one explanation for this phenomenon is a physiologic gender-based difference in the function of the renin-angiotensin system (RAS). This system is an important mediator of renal and cardiovascular physiology and pathophysiology (2,3), and angiotensin II (AngII) is its principal effector. Studies from our laboratory have demonstrated distinct gender differences in RAS function (4 -7). In vivo findings in the canine have shown that estrogen replacement after ovariectomy reduces AngII type 1 (AT 1 ) receptor number in several tissues, including kidney (8). Studies in mouse models of vascular disease have suggested that estrogen and AngII receptor blockers (ARB) act synergistically on several outcomes, including atherosclerotic changes (9) and neointimal thickening after vascular injury (10).Taken together, these experiments in the animal and human models suggest a possible synergistic effect between ARB and estrogen. We therefore examined AT 1 receptor blockade by ARB in young, healthy men and women. It was hypothesized that such a synergistic effect would manifest in gender differences in the extent to which ARB administration results in decreased AngII sensitivity and reduced receptor expression (11,12). These experiments w...

Gender Differences in Pressure-Natriuresis and Renal Autoregulation

“…35 It has been speculated that activation of the AT 2 R or NO or both could be mediating these effects. 34,35 Our results are consistent with such a conclusion.…”

“…In a study performed by Miller et al 33 that examined the renal response of young healthy subjects to graded Ang II infusion, GFR was maintained in men, whereas in women GFR declined. More recently, Miller et al 34 demonstrated that in the presence of AT 1 R blockade, women exhibited a significantly blunted RBF response to Ang II compared to men. Sexual dimorphism in the nonmodulation phenotype of hypertension, 35 which is characterized by a lowered RBF response to Ang II with a high-salt diet, also has been observed.…”

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

“…Polymorphism of the AT 2 R receptor has been associated with hypertension in premenopausal women but not in men. 30 Furthermore, on a background of AT 1 R blockade, the renal response to Ang II infusion was attenuated more in women than in men, suggesting a role for the AT 2 R. 31 Supporting these findings, we found that the female WT mice had a 3-fold higher basal AT 2 R expression compared with males ( Figure 3). Importantly, in the current study, basal mRNA expression levels of the AT 1a R and the AT 1b R were not different between the males and females and increased by the same magnitude in response to Ang II and, thus, do not seem to contribute to the attenuated pressor response to Ang II in the WT females.…”

Age is a determinant of acute hemodynamic responses to hyperglycemia and angiotensin II in humans with uncomplicated type 1 diabetes mellitus

“…These previous observational studies are consistent with our findings, since SBP was higher and DBP lower in the two youngest groups of DM vs. control subjects. Although our study did not define the mechanisms responsible for exaggerated ANG II responses in older diabetic subjects, the augmented response may have been due to ANG II type 1 receptor upregulation, which can increase ANG II sensitivity in humans (14,21). AT 1 receptor upregulation, which has been observed in aging human vascular tissue, may have been due to the observed declines in circulating RAS mediators or to DM-related increased AT 1 receptor mRNA expression and signaling (14,31,32).…”

“…Between group differences in renal hemodynamic responses to hyperglycemia and ANG II were determined by repeated measures ANOVA. We controlled for baseline between group differences in hemodynamic parameters by entering these factors into a multivariate stepwise regression analysis, and we controlled for the effects of gender and body mass index (BMI) on renal function by including these factors in the statistical model (21,(27)(28)(29). In the primary analysis, we included the entire 66 member cohort and did not correct for differences in diabetes duration.…”