TY - JOUR
T1 - Bile acid G protein-coupled membrane receptor TGR5 modulates aquaporin 2-mediated water homeostasis
AU - Li, Suchun
AU - Qiu, Miaojuan
AU - Kong, Yonglun
AU - Zhao, Xiaoduo
AU - Choi, Hyo Jung
AU - Reich, Maria
AU - Bunkelman, Brady H.
AU - Liu, Qiaojuan
AU - Hu, Shan
AU - Han, Mengke
AU - Xie, Haixia
AU - Rosenberg, Avi Z.
AU - Keitel, Verena
AU - Kwon, Tae Hwan
AU - Levi, Moshe
AU - Li, Chunling
AU - Wang, Weidong
N1 - Funding Information:
This work was supported by the National Natural Science Foundation of China (grants 81670646 and 81570635), Natural Science Foundation of Guangdong Province (grants 2016A020215034 and 2014A030313168), Natural Science Foundation of Guangzhou (grant 201707010036), and the International Cooperation Program Fund of Sun Yat-Sen University (grant 02300-31145400). This work was also supported by the National Research Foundation of Korea funded by the Ministry of Science, Information and Communication Technology and Future Planning, Korea (grants 2016R1A2B4009365 and 2017R1D1A3B03032262), Deutsche Forschungsgemeinschaft through Sonderforschungsbereich 974, and National Institutes of Health grants R01AG049493, R01DK098336, and R01DK116567.
Publisher Copyright:
© 2018 by the American Society of Nephrology.
PY - 2018/11
Y1 - 2018/11
N2 - 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 signalingon aquaporin-2 (AQP2) expression, and examined the in vivo effectsof 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 innermedulla. 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.
AB - 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 signalingon aquaporin-2 (AQP2) expression, and examined the in vivo effectsof 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 innermedulla. 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.
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U2 - 10.1681/ASN.2018030271
DO - 10.1681/ASN.2018030271
M3 - Article
C2 - 30305310
AN - SCOPUS:85055822361
SN - 1046-6673
VL - 29
SP - 2658
EP - 2670
JO - Journal of the American Society of Nephrology : JASN
JF - Journal of the American Society of Nephrology : JASN
IS - 11
ER -