Estradiol Facilitates a More Rapid Natriuretic Response to a High Salt Diet in Female Rats
Authors: Gohar Eman Y. , Pollock David M. 
Published: November 2023

Salt‐sensitive hypertension and renal diseases are more prevalent in postmenopausal women compared to premenopause, suggesting a central role for ovarian hormones in cardiovascular and renal protection. Our overall goal was to determine whether ovarian hormones contribute to renal adjustments to a high salt diet. Our initial experiments showed that increasing dietary Na+ intake causes a more rapid natriuretic response in female Sprague Dawley rats compared to age‐matched males. Given the central role of endothelin‐1 (ET‐1) in Na+ homeostasis and blood pressure control, we tested the hypothesis that estradiol (E2) and/or progesterone (P) regulate ET‐1 and renal Na+ handling in female rats. Male and female rats were placed on normal salt (NS, 0.49% NaCl) followed by high salt (HS, 4% NaCl) diet for 5 days. On NS diet, females had slightly higher urinary Na+ excretion (UNaV) compared to males. In parallel, urinary ET‐1 excretion (UET‐1V) was significantly higher in females compared to males (14.1±3.8 vs. 5.6±1.0 pg/kg/day, respectively, p<0.05). On the initial two days of increasing the dietary Na+ intake, females showed a significantly enhanced natriuretic effect compared to males. Only males showed significant increases in UET‐1V on HS diet compared to NS diet (10.2±0.8 vs 5.6±1.0 pg/kg/day, respectively, p<0.05), whereas, females maintained the already elevated UET‐1V. A separate series of female rats were either sham operated or ovariectomized and implanted with 21‐day controlled release pellets containing 0.35 mg E2 (OVX+E2), 25 mg P (OVX+P), both (OVX+E2+P) or placebo (OVX). Ovariectomy did not have a significant effect on basal UNaV or UET‐1V; however, OVX+E2 and OVX+E2+P had significantly higher UNaV compared to OVX rats on NS diet (5.0±0.4 and 5.8±0.3 vs 3.0+0.3 mmol/kg/day, respectively, p<0.05), whereas P supplementation of OVX rats did not affect UNaV. Interestingly, UET‐1V was significantly enhanced in OVX+E2+P rats compared to OVX rats (54.5±4.5 vs 16.7+4.0 pg/kg/day, respectively, p<0.05), but was not affected by E2 or P alone in OVX rats fed NS. Importantly, the enhanced HS‐induced natriuresis demonstrated in sham females was blunted in OVX or OVX+P rats and restored in OVX+E2 or OVX+E2+P. Circulating sex hormones, electrolytes and ET‐1 were also determined under NS and HS diets. Circulating ET‐1 levels were not sexually dimorphic under NS or HS diets. However, OVX rats fed NS had significantly higher circulating ET‐1 compared to sham rats (0.83±0.07 vs. 0.54±0.04 pg/ml, respectively) and hormonal replacement with E2 and/or P did not normalize the levels of circulating ET‐1. HS diet caused significant increases in circulating ET‐1 only in OVX rats (1.20±0.07 vs. 0.83±0.07 pg/ml, respectively). Collectively, these data indicate that female rats are better able to adapt to increased dietary Na+ intake compared to males and highlight important roles for ovarian hormones, particularly E2, in this sexual dimorphism. The ET‐1 system and probably other natriuretic pathways appear to be playing a role in sex‐differences in natriuresis with increased dietary Na+ intake.

These studies were funded by AHA postdoctoral grant (15POST25090329 to EYG) and NIH grant (P01 HL95499 to DMP).