Demographic studies reveal lower prevalence of hypertension among premenopausal females compared to age-matched males. The kidney plays a central role in the maintenance of sodium (Na+) homeostasis and consequently blood pressure. Renal 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 renal medullary G protein-coupled estrogen receptor 1 (GPER1) promotes ET-1-dependent natriuresis in female, but not male, rats. We hypothesized that GPER1 upregulates the renal ET-1 signaling system in females, but not males. To test our hypothesis, we determined the effect of GPER1 deletion on ET-1 and its downstream effectors in the renal cortex, outer and inner medulla obtained from 12–16-week-old female and male mice. GPER1 knockout (KO) mice and wildtype (WT) littermates were implanted with telemetry transmitters for blood pressure assessment, and we used metabolic cages to determine urinary Na+ excretion. GPER1 deletion did not significantly affect 24-h mean arterial pressure (MAP) nor urinary Na+ excretion. However, GPER1 deletion decreased urinary ET-1 excretion in females but not males. Of note, female WT mice had greater urinary ET-1 excretion than male WT littermates, whereas no sex differences were observed in GPER1 KO mice. GPER1 deletion increased inner medullary ET-1 peptide content in both sexes but increased outer medullary ET-1 content in females only. Cortical ET-1 content increased in response to GPER1 deletion in both sexes. Furthermore, GPER1 deletion notably increased inner medullary ET receptor A (ETA) and decreased outer medullary ET receptor B (ETB) mRNA expression in male, but not female, mice. We conclude that GPER1 is required for greater ET-1 excretion in females. Our data suggest that GPER1 is an upstream regulator of renal medullary ET-1 production and ET receptor expression in a sex-specific manner. Overall, our study identifies the role of GPER1 as a sex-specific upstream regulator of the renal ET-1 system.

Cardiovascular (CV) and renal diseases are increasingly prevalent in the United States and globally. CV-related mortality is the leading cause of death in the United States, while renal-related mortality is the 8th. Despite advanced therapeutics, both diseases persist, warranting continued exploration of disease mechanisms to develop novel therapeutics and advance clinical outcomes for cardio-renal health. CV and renal diseases increase with age, and there are sex differences evident in both the prevalence and progression of CV and renal disease. These age and sex differences seen in cardio-renal health implicate sex hormones as potentially important regulators to be studied. One such regulator is G protein-coupled estrogen receptor 1 (GPER1). GPER1 has been implicated in estrogen signaling and is expressed in a variety of tissues including the heart, vasculature, and kidney. GPER1 has been shown to be protective against CV and renal diseases in different experimental animal models. GPER1 actions involve multiple signaling pathways: interaction with aldosterone and endothelin-1 signaling, stimulation of the release of nitric oxide, and reduction in oxidative stress, inflammation, and immune infiltration. This review will discuss the current literature regarding GPER1 and cardio-renal health, particularly in the context of aging. Improving our understanding of GPER1-evoked mechanisms may reveal novel therapeutics aimed at improving cardio-renal health and clinical outcomes in the elderly.

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.