Metabolism | Wang Weidong and Li Chunling's Team Reveal That the Bile Acid Membrane Receptor TGR5 Can Regulate Renal ENaC to Improve Hypertension
In recent years, salt-sensitive hypertension has become a significant public health issue. Salt-sensitive hypertension increases the risk of cardiovascular diseases and is an independent risk factor for cardiovascular diseases and all-cause mortality. Salt-sensitive hypertension is closely related to the impairment of the renal natriuretic mechanism. The dysregulation of the renal epithelial sodium channel (ENaC) protein is one of the important pathophysiological mechanisms for the development of salt-sensitive hypertension.
Hypertension is associated with liver function and gut microbiota. Growing evidence shows that bile acids are involved in regulating the physiological and pathophysiological functions of multiple tissues and organs in the body through receptor-dependent and non-receptor-dependent forms, such as metabolic regulation, anti-inflammation, and anti-fibrosis. Recently, the research groups led by Wang Weidong and Li Chunling demonstrated that the activation of the bile acid G-protein-coupled membrane receptor (TGR5) expressed in the principal cells of the renal collecting ducts is involved in regulating the reabsorption of water in the kidneys, thereby affecting blood volume and blood pressure. In January 2025, this research group published an article titled "TGR5 attenuates DOCA-salt hypertension through regulating histone H3K4 methylation of ENaC in the kidney" in the classic journal Metabolism - Clinical and Experimental, further revealing the molecular mechanism by which TGR5 is involved in regulating renal sodium reabsorption and excretion, as well as its potential role in intervening in the development of salt-sensitive hypertension.
In DOCA-salt-induced hypertensive mice, endogenous or exogenous TGR5 receptor agonists lithocholic acid or INT-777 significantly reduced blood pressure levels and decreased the expression of renal ENaC protein and genes. TGR5 gene knockout significantly increased blood pressure and renal ENaC expression in DOCA-salt mice. In mpkCCD cells of the renal cortical collecting ducts, the activation of the TGR5 receptor significantly inhibited aldosterone-induced ENaC-mediated sodium influx and decreased the expression of ENaC protein and genes. Through the analysis of chromosomal modifications, it was found that there is a trimethylation modification of lysine at the fourth position of histone H3 (H3K4me3) at the transcriptional start site of the ENaC gene. ChIP-seq analysis and molecular biology experiments showed that there is H3K4me3 enrichment in the renal ENaC gene of DOCA-salt mice, and the activation of TGR5 significantly reversed this enrichment. Further research indicated that the activation of TGR5 significantly reduced the expression and activity of renal histone demethylase 5A (KDM5A), suggesting that TGR5 may be involved in regulating the transcription and translation of ENaC by affecting histone demethylase 5A, thereby regulating renal sodium reabsorption and influencing blood pressure.
This study provides important experimental evidence for the regulatory role of the bile acid receptor TGR5 in salt-sensitive hypertension and reveals the molecular mechanism by which TGR5 regulates ENaC expression. This discovery not only deepens the understanding of the pathogenesis of salt-sensitive hypertension but also provides new ideas for the research on renal water and sodium metabolism and blood volume regulation, offering new potential targets for the treatment of hypertension.
The co-first authors of this study are Xu Long, a Ph.D. in Physiology from Zhongshan School of Medicine, and Wu Xinyan, a Ph.D. candidate in Pathophysiology. The corresponding authors also include Dr. Wang Lei from Guangzhou University of Chinese Medicine.
Original link: https://www.metabolismjournal.com/article/S0026-0495(25)00002-2/fulltext
