MicroRNA-19 is regulated by aldosterone in a sex-specific manner to alter kidney sodium transport

A key regulator of blood pressure homeostasis is the steroid hormone aldosterone, which is released as the final signaling hormone of the renin-angiotensin-aldosterone-signaling (RAAS) system. Aldosterone increases sodium (Na⁺) reabsorption in the kidney distal nephron to regulate blood volume. Unregulated RAAS signaling can lead to hypertension and cardiovascular disease. The serum and glucocorticoid kinase (SGK1) coordinates much of the Na⁺ reabsorption in the cortical collecting duct (CCD) tubular epithelial cells. We previously demonstrated that aldosterone alters the expression of microRNAs (miRs) in CCD principal cells. The aldosterone-regulated miRs can modulate Na⁺ transport and the cellular response to aldosterone signaling. However, the sex-specific regulation of miRs by aldosterone in the kidney distal nephron has not been explored. In this study we report that miR-19, part of the miR-17~92 cluster, is upregulated in female mouse CCD cells in response to aldosterone activation. Mir-19 binding to the 3'-untranslated region of SGK1 was confirmed using a dual-luciferase reporter assay. Increasing miR-19 expression in CCD cells decreased SGK1 expression. Removal of this cluster using a nephron-specific, inducible knockout mouse model increased SGK1 expression in female mouse CCD cells. The miR-19-induced decrease in SGK1 protein expression, reduced the response to aldosterone stimulation, and may account for sex-specific differences in aldosterone signaling. 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.