Gender-dependent renal hemodynamic responses to angiotensin 1-7 following AT1 receptor blockade and chronic renal denervation in rats

Abstract

Introduction : The sympathetic nervous system (SNS) and the renin-angiotensin system (RAS) play important roles in regulating renal hemodynamics. Given the complexity of these two systems, a deeper understanding of their interplay may yield valuable insights for developing innovative therapeutic strategies aimed at managing cardiovascular and renal disorders and preserving kidney function. This study investigated the renal hemodynamic responses to Angiotensin-(1-7) (Ang-(1-7)) in intact and chronically denervated male and female rats, with or without Angiotensin II type 1 receptor (AT1R) blockade. Methods : A total of 54 Wistar rats (26 males, 28 females) underwent right nephrectomy and were assigned to intact or chronic renal denervation (CRDN) groups. Each group received either saline or losartan, followed by graded Ang-(1-7) infusions. Mean arterial pressure (MAP), renal perfusion pressure (RPP), renal blood flow (RBF), and renal vascular resistance (RVR) were recorded. RPP was controlled during Ang-(1-7) infusion, and female rats were studied during the diestrus phase. Results : At baseline, a significant increase in RVR and a decrease in RBF were observed in both male and female CRDN groups. The compensatory kidney hypertrophy was detected in denervated rats. Changes in renal hemodynamic parameters, including RBF and RVR, in saline- or losartan-treated groups of both sexes showed no significant differences between intact and CRDN groups before Ang-(1-7) administration. However, Ang-(1-7) infusion elevated RBF (P-dose = 0.03) and attenuated RVR (P-dose = 0.027) in male rats treated with saline or losartan (RBF; P-dose = 0.001, RVR; P-dose < 0.001), but this response was only significantly different between intact and CRDN male rats treated with losartan (RBF; P-group = 0.01, RVR; P-group = 0.002). Such findings were not observed in female rats. Serum nitrite levels were significantly reduced (P-group = 0.04) in male CRDN rats treated with losartan compared to the corresponding intact group. Conclusion : AT1R blockade unmasks a Mas receptor (MasR)-dependent vasodilatory pathway for Ang-(1-7) that is neurally gated in males but estrogen-dependent in females. These findings highlight a sex-dependent neuro-hormonal mechanism that may underlie variable outcomes of renal denervation therapies.