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
复制标题
胆汁酸 G 蛋白偶联膜受体 TGR5 调节水通道蛋白 2 介导的水稳态
DOI：
10.1681/asn.2018030271
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发表时间：
2018-11-01
影响因子：
13.6
通讯作者：
Wang, Weidong
中科院分区：
文献类型：
--
作者：
Li, Suchun;Qiu, Miaojuan;Wang, Weidong
背景胆汁酸激活受体包括膜G蛋白偶联受体TGR 5和核法尼醇X受体（FXR），在肾脏疾病中发挥作用。本研究旨在探讨TGR 5在肾脏水处理中的作用及其分子机制。方法采用大鼠肾脏内髓集合管（IMCD）细胞悬液，研究TGR 5信号通路对水通道蛋白2（AQP 2）表达的影响，并检测了TGR 5在患有锂诱导的肾源性尿崩症（NDI）和TGR 5敲除的小鼠中的体内作用结果TGR 5被内源性TGR 5配体石胆酸（LCA）或合成的TGR 5特异性激动剂INT-777激活后，通过cAMP-蛋白激酶A信号通路诱导大鼠IMCD细胞中的AQP 2表达和细胞内运输。在NDI小鼠中，饮食中补充LCA显著减少尿量和增加尿渗透压，这与肾脏内髓质中AQP 2表达显著上调相关。补充内源性FXR激动剂没有影响。在锂给药大鼠的原代IMCD混悬液中，INT-767（FXR和TGR 5双重激动剂）或INT-777（而非INT-747（FXR激动剂））给药可增加AQP 2表达。Tgr 5（-/-）小鼠脱水后浓缩尿液的能力减弱，这与肾脏髓质AQP 2表达减少有关。在锂处理的Tgr 5（-/-）小鼠，LCA治疗未能防止减少AQP 2 expression.Conclusions肾脏AQP 2的表达增加TGR 5刺激和改善受损的尿浓度在锂诱导的NDI。因此，TGR 5参与调节肾脏中的水代谢。
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 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.