1. Academic Validation
  2. Bile Acid G Protein-Coupled Membrane Receptor TGR5 Modulates Aquaporin 2-Mediated Water Homeostasis

Bile Acid G Protein-Coupled Membrane Receptor TGR5 Modulates Aquaporin 2-Mediated Water Homeostasis

  • J Am Soc Nephrol. 2018 Nov;29(11):2658-2670. doi: 10.1681/ASN.2018030271.
Suchun Li 1 Miaojuan Qiu 1 Yonglun Kong 1 Xiaoduo Zhao 1 Hyo-Jung Choi 2 Maria Reich 3 Brady H Bunkelman 4 Qiaojuan Liu 1 Shan Hu 1 Mengke Han 1 Haixia Xie 1 Avi Z Rosenberg 4 5 Verena Keitel 3 Tae-Hwan Kwon 2 Moshe Levi 6 Chunling Li 7 Weidong Wang 7
Affiliations

Affiliations

  • 1 Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
  • 2 Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Taegu, Korea.
  • 3 Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty at Heinrich-Heine-University, Düsseldorf, Germany.
  • 4 Department of Pathology and.
  • 5 Division of Kidney Urologic Pathology, Johns Hopkins University, Baltimore, Maryland; and.
  • 6 Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, DC.
  • 7 Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; [email protected] [email protected].
Abstract

Background: The bile acid-activated receptors, including the membrane G protein-coupled receptor TGR5 and nuclear farnesoid X receptor (FXR), have roles in kidney diseases. In this study, we investigated the role of TGR5 in renal water handling and the underlying molecular mechanisms.

Methods: We used tubule suspensions of inner medullary collecting duct (IMCD) cells from rat kidneys to investigate the effect of TGR5 signaling on aquaporin-2 (AQP2) expression, and examined the in vivo effects of TGR5 in mice with lithium-induced nephrogenic diabetes insipidus (NDI) and Tgr5 knockout (Tgr5-/-) mice.

Results: Activation of TGR5 by lithocholic acid (LCA), an endogenous TGR5 ligand, or INT-777, a synthetic TGR5-specific agonist, induced AQP2 expression and intracellular trafficking in rat IMCD cells via a cAMP-protein kinase A signaling pathway. In mice with NDI, dietary supplementation with LCA markedly decreased urine output and increased urine osmolality, which was associated with significantly upregulated AQP2 expression in the kidney inner medulla. Supplementation with endogenous FXR Agonist had no effect. In primary IMCD suspensions from lithium-treated rats, treatment with INT-767 (FXR and TGR5 dual agonist) or INT-777, but not INT-747 (FXR Agonist), increased AQP2 expression. Tgr5-/- mice exhibited an attenuated ability to concentrate urine in response to 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.

Conclusions: TGR5 stimulation increases renal AQP2 expression and improves impaired urinary concentration in lithium-induced NDI. TGR5 is thus involved in regulating water metabolism in the kidney.

Keywords

AQP2; TGR5; cAMP; lithium.

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