TGR5 attenuates DOCA-salt hypertension through regulating histone H3K4 methylation of ENaC in the kidney

Abstract

Epithelial sodium channel (ENaC), located in the collecting duct principal cells of the kidney, is responsible for the reabsorption of sodium and plays a critical role in the regulation of extracellular fluid volume and consequently blood pressure. The G protein-coupled bile acid receptor (TGR5) is a membrane receptor mediating effects of bile acid and is implicated in kidney diseases. The current study aims to investigate whether TGR5 activation in the kidney regulated ENaC expression and potential mechanism. Lithocholic acid (LCA), a TGR5 agonist, markedly decreased systolic blood pressure induced by DOCA-salt in mice, which was associated with decreased ENaC expression in the kidney. DOCA-salt treatment increased renal expression of histone H3 lysine 4 trimethylation (H3K4me3) and decreased expression of lysine-specific demethylase 5A (KDM5A), a lysine demethylase, which was markedly reversed by LCA. TGR5 knockout caused further increased systolic blood pressure and ENaC expression in mice with DOCA-salt in association with increased H3K4me3 and decreased KDM5A. In immortalized mouse cortical collecting duct (mpkCCD) cells LCA markedly inhibited aldosterone-induced ENaC-mediated current. LCA treatment or TGR5 overexpression markedly inhibited ENaC and H3K4me3 protein expression in association with decreased KDM5A in mpkCCD cells treated with either aldosterone or angiotensin II. Inhibition or knockdown of KDM5A in mpkCCD cells prevented LCA-induced downregulation of ENaC expression by promoting H3K4me3 on the ENaC transcription start site. LCA upregulated KDM5A expression was likely through JNK/c-Jun signal pathway. In conclusion, LCA decreased blood pressure and ENaC protein expression in the kidney of mice with DOCA-salt, likely through activating TGR5 and upregulating KDM5A-induced H3K4me3 demethylation in ENaC promoter region.