Bile Acid Membrane Receptor TGR5 Regulates Renal AQP2 and Improves Lithiuminduced NDI

Abstract

The bile acid‐activated receptors, which include the membrane G protein‐coupled receptor (TGR5) and nuclear farnesoid X receptor (FXR), are shown to play roles in kidney diseases. The purpose of current study was to investigate the role of TGR5 receptors in renal water handling and the underlying molecular mechanisms. The activation of TGR5 by lithocholic acid (LCA, a TGR5 endogenous ligand) induced aquaporin‐2 (AQP2) protein expression and intracellular trafficking in rat primary cultured inner medullary collecting duct (IMCD) cells via cAMP‐PKA signaling pathway. A synthetic specific TGR5 agonist INT‐777 has the same effects as LCA in IMCD cells. In mice with lithium‐induced nephrogenic diabetes insipidus (NDI), the activation of TGR5 by LCA markedly decreased urine output and increased urine osmolality, which was associated with significantly up‐regulated AQP2 expression in the inner medulla, whereas chenodeoxycholic acid (CDCA, a FXR endogenous ligand) had no effects. In primary cultured IMCD cells prepared from lithium‐treated rats, INT‐777 or INT‐767 (a FXR and TGR5 dual agonist), but not INT‐747 (a FXR agonist) increased AQP2 protein expression. Compared with wildtype mice, tgr5−/− mice exhibited a mild urine concentration defect after dehydration, which was associated with decreased AQP2 expression in the kidney inner medulla. In lithium‐treated tgr5−/− mice, LCA treatment failed to prevent reduction of AQP2 expression. In conclusion, TGR5 activation increases renal AQP2 expression via cAMP‐PKA signaling pathway and improves impaired urinary concentration in lithium‐induced NDI. TGR5 is thus involved in regulation of water metabolism in the kidney.Support or Funding InformationThis work was supported by the Natural Science Foundation of China (Grants 81370822, 81570635, and 81670646), by the 111 Project, China (No. B13037), and by the Natural Science Foundation of Guangdong Province, China (Grants 2014A020212623, 2014A030313168, and 2016A020215034).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.