G Protein‐Coupled Estrogen Receptor 1 is Required for Greater Endothelin‐1 Excretion in Female Mice

Abstract

Estrogen signaling via G protein‐coupled estrogen receptor 1 (GPER1) can elicit cardiovascular and renal protective actions. Endothelin‐1 (ET‐1) is a pro‐natriuretic peptide that contributes to sex differences in blood pressure regulation and Na+ homeostasis. We recently showed that activation of GPER1 in the renal medulla promotes ET‐1‐dependent natriuresis in female but not male rats. Also, renal GPER1 expression is significantly higher in female rats than in male rats. In the current study, we hypothesized that genetic deletion of GPER1 would elevate blood pressure and impair renal ET‐1 production/release in a sex‐specific manner. Twelve‐week‐old male and female GPER1‐knockout (KO) and wild‐type (WT) littermate mice were implanted with telemeters to monitor blood pressure. Parallel groups of mice were placed into metabolic cages, and 24‐h urine samples were collected while food and water intake were monitored. Then, animals were euthanized to obtain plasma. Urinary levels of electrolytes and ET‐1 were measured. GPER1 deletion did not significantly affect mean arterial blood pressure in female (KO: 102±1 mmHg; WT: 102±2 mmHg; n=7‐8/group, p=0.9) or male mice (KO: 106±3 mmHg; WT: 106±2 mmHg; n=6‐10/group, p=1). No genotypic differences were observed in food intake, water intake, or urine flow rate. GPER1 deletion did not significantly affect urinary Na+excretion in female (KO: 0.25±0.05 μg/24 h; WT: 0.17±0.05 μg/24 h; n=9‐12/group, p=0.52) or male mice (KO: 0.34±0.06 μg/24 h; WT: 0.35±0.04 μg/24 h; n=10‐12/group, p=1.00). Similarly, GPER1 deletion did not affect urinary K+ excretion in either sex. However, GPER1 deletion decreased urinary ET‐1 excretion in females (KO: 75.16±16.35 ng/24 h; WT: 172.83±24.67 ng/24 h; n=6‐10/group, p<0.005) but not males (KO: 95.18±17.52 ng/24 h; WT: 76.03± 9.90 ng/24 h; n=10‐12/group, p=0.69). Of note, WT females had significantly greater urinary ET‐1 excretion than WT males (p=0.001), whereas KO mice had no sex differences in ET‐1 excretion. Importantly, urinary excretion of ET‐1 reflects intrarenal ET‐1 production/release. GPER1 deletion did not significantly change plasma ET‐1 concentration in either sex. Finally, GPER1 deletion did not affect urinary aldosterone excretion in females (KO: 315.98±73.13 pg/24 h; WT: 306.79±81.45 pg/24 h; n=7‐8, p=1.00) or males (KO: 544.09±130.20 pg/24 h; WT: 481.84±68.30 pg/24 h; n=8/group, p=0.87). However, male mice had significantly greater urinary aldosterone excretion than female mice (p=0.04), regardless of genotype. Overall, we demonstrate that WT female mice have higher urinary ET‐1 excretion than WT males, and that GPER1 deletion eliminates this sex‐related difference in intrarenal ET‐1 production/release. Our data suggest that GPER1 may contribute to the enhanced capacity of the female kidney to maintain Na+ homeostasis and have led us to hypothesize this as a mechanism for protecting females against salt‐sensitive hypertension.