The miR-17~92 cluster regulates aldosterone signaling: Contributions to sex differences in sodium transport in the distal nephron

Hypertension affects over a billion individuals globally, with aldosterone playing a crucial role in blood pressure regulation through the renin-angiotensin-aldosterone-signaling (RAAS) system. Premenopausal women exhibit a lower risk of hypertension than age-matched men, attributed to both reduced aldosterone levels and estrogen signaling. While our previous work highlighted aldosterone's influence on microRNA (miR) expression in collecting duct epithelial cells, the sex-specific regulation of miRs and their impact on sex differences in blood pressure homeostasis remain unexplored. This study investigates the hypothesis that the miR-17~92 cluster contributes to sex differences in aldosterone signaling within the nephron's collecting duct epithelia. Using in vitro and in vivo models, we examined the response of miR-17~92 to aldosterone and estrogen stimulation. MiR-19, a component of miR-17~92, showed upregulation in response to both aldosterone and estrogen in cultured cells. In vivo, a sex-specific upregulation of the miR-17~92 cluster was evident in female mice on a low-Na+ diet, stimulating aldosterone release. In mCCD cells, estrogen pretreatment attenuated aldosterone stimulation by targeting the serum and glucocorticoid-induced kinase (Sgk1) mRNA. However, neither estrogen receptors (ERs) nor xenobiotic receptors (XRs) were responsible for this effect. Luciferase assays confirmed the binding of miR-19 to the 3’-UTR of Sgk1. Overexpression of miR-19 in cells inhibited aldosterone-induced Na+ transport, while inhibition of miR-19 had the opposite effect. In vivo studies on mice corroborated the sex-specific regulation of Sgk1 by miR-17~92. Female mice exhibited an elevation in relative Sgk1 expression compared to males when placed on low Na+ diets. By examining evolution of the miR-17~92 cluster, phylogenetic sequence analysis indicated that this cluster arose at the same time that other Na+-sparing and salt regulatory proteins, specifically SGK1 first emerged, indicating a conserved role for these miRs in kidney function of salt and water homeostasis. In conclusion, our findings suggest that the miR-17~92 cluster may contribute to sex-specific differences in aldosterone signaling, providing insights into the molecular mechanisms underlying sex disparities in blood pressure regulation.