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

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. Thus, renal GPER1 functionally interacts with ENaC in a sex-specific manner to promote natriuresis.