Abstract: FR-PO526
TGR5 Activation Ameliorated Hypertension Through Inhibiting Epithelial Sodium Channel (ENaC) Expression in the Kidney of Deoxycorticosterone Acetate (DOCA) Salt-Treated Mice
Session Information
- Fluid, Electrolyte, Acid-Base Disorders: Basic
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Fluid, Electrolytes, and Acid-Base Disorders
- 1101 Fluid, Electrolyte, and Acid-Base Disorders: Basic
Authors
- Xu, Long, Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
- Wu, Xinyan, Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
- Li, Suchun, Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
- Chen, Wei, Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Wang, Lei, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
- Li, Chunling, Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
- Wang, Weidong, Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
Background
Epithelial sodium channel (ENaC), located in the collecting duct principal cells of the kidney, plays a critical role in regulating sodium balance and blood pressure in the body. The G protein-coupled bile acid receptor (TGR5) is a cell-surface receptor mediating bile acid effects and is implicated in several kidney diseases. The current study aims to investigate whether activation of TGR5 by lithocholic acid (LCA) regulated renal ENaC expression and blood pressure in deoxycorticosterone acetate (DOCA)-salt induced hypertensive mice.
Methods
Hypertension was induced in mice by subcutaneous implantation of DOCA pellets with 1% NaCl in drinking water. LCA was given by gavage.
Results
LCA markedly decreased blood pressure induced by DOCA-salt in mice, which was associated with decreased expression levels of ENaC mRNA and protein in the kidney. Compared with wild type group, TGR5 knockout mice developed increased blood pressure and ENaC protein expression in the kidney after DOCA-salt treatment. Bioinformatic indicates H3K4me1,2,3 enrichment in the promotor of ENaC. DOCA-salt treatment was associated with increased H3K4me3 expression in the kidney cortex which was markedly inhibited by LCA, while TGR5 knockout caused further increased H3K4me3 expression mice with DOCA-salt. Interestingly the mRNA and protein expression of KDM5A, a lysine demethylase, was significantly decreased in the kidney of mice with DOCA-salt, which was also significantly prevented by LCA. These data likely suggests that TGR5 activation decreased H3K4me3 enrichment of ENaC thus downregulated ENaC mRNA and protein expression. In immortalized mouse cortical collecting duct cells (mpkCCD) cells treated with either Ang II or aldosterone, the protein and mRNA expression levels of ENaC subunits were dramatically increased in association with increased protein expression of H3K4me3 and decreased mRNA and protein abundance of KDM5A, which were all inhibited by LCA treatment. Inhibition of KDM5 or KDM5A knockdown in mpkCCD cells treated with Ang II or aldosterone prevented the downregulation of ENaC expression induced by LCA.
Conclusion
In conclusion, LCA decreased blood pressure and ENaC protein expression in the kidney of mice with DOCA-salt, likely through increased KDM5A-mediated H3K4me3.
Funding
- Government Support – Non-U.S.