Renal G Protein-Coupled Estrogen Receptor 1 Regulates the Epithelial Sodium Channel Promoting Natriuresis to a Greater Extent in Females

Authors

Victoria L Nasci
Jean C Bopassa
Elena Mironova
Megan Rhoads
Ravneet Singh
Dennis P Buehler
David M Pollock
Oleh M Pochynyuk
James D Stockand
Eman Y Gohar

Language

English

Publication Date

7-1-2025

Journal

American Journal of Physiology-Renal Physiology

DOI

10.1152/ajprenal.00019.2025

PMID

40402842

PMCID

PMC12208778

PubMedCentral® Posted Date

7-1-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

Hypertension prevalence is lower in women than men. Enhanced renal sodium (Na+) handling in females has been implicated in sex-differences in hypertension. Epithelial Na+ channel (ENaC) is a key contributor to Na+ homeostasis and is regulated by estrogen. Recent evidence suggests G protein-coupled estrogen receptor 1 (GPER1) evokes a female-specific natriuresis that involves endothelin-1 (ET-1). ET-1 has been shown to downregulate ENaC activity, but whether GPER1 regulates ENaC to modulate natriuresis is unknown. We tested the hypothesis that renal GPER1 functionally interacts with ENaC to promote natriuresis in a sex-specific manner. RNAscope confirmed co-expression of GPER1 and ENaC in rat renal tubules in a sex and region-specific manner. Within the renal medulla, the number of ENaC/GPER1-positive tubules was greater in females than males. Renal medullary inhibition of ENaC or activation of GPER1 evoked comparable natriuresis in female rats. Electrophysiology revealed that pharmacologic GPER1 activation downregulated ENaC activity, whereas genetic deletion of GPER1 from the principal cells of the collecting duct caused ENaC hyperactivity. The hyperactivity of ENaC caused by deletion of GPER1 in the principal cells was greater in female than male mice. RNAscope co-expression of AQP2 and GPER1 confirmed the KO of GPER1 from the PCs in the kidney. Thus, renal GPER1 functionally interacts with ENaC in a sex-specific manner to promote natriuresis.

Keywords

Animals, Epithelial Sodium Channels, Receptors, G-Protein-Coupled, Female, Natriuresis, Male, Mice, Mice, Inbred C57BL, Rats, Sprague-Dawley, Mice, Knockout, Sex Factors, Aquaporin 2, Rats, Kidney, Receptors, Estrogen, Endothelin-1, Sodium, GPER1, ENaC, sodium homeostasis, natriuresis, sex differences, hypertension

Published Open-Access

yes

Recommended Citation

Nasci, Victoria L; Bopassa, Jean C; Mironova, Elena; et al., "Renal G Protein-Coupled Estrogen Receptor 1 Regulates the Epithelial Sodium Channel Promoting Natriuresis to a Greater Extent in Females" (2025). Faculty, Staff and Student Publications. 6433.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/6433