Farnesoid X receptor (FXR) gene deficiency impairs urine concentration in mice
Farnesoid X receptor (FXR) gene deficiency impairs urine concentration in mice
复制标题
DOI：
10.1073/pnas.1323977111
复制
发表时间：
2014-01
期刊：
影响因子：
--
通讯作者：
Xiaoyan Zhang;Shizheng Huang;Min Gao;Jia Liu;Xiao Jia;Qifei Han;Senfeng Zheng;Yi-fei Miao;Shuo Li;H. Weng;X. Xia;Shengnan Du;Wan-fu Wu;J. Gustafsson;Y. Guan
中科院分区：
文献类型：
--
作者：
Xiaoyan Zhang;Shizheng Huang;Min Gao;Jia Liu;Xiao Jia;Qifei Han;Senfeng Zheng;Yi-fei Miao;Shuo Li;H. Weng;X. Xia;Shengnan Du;Wan-fu Wu;J. Gustafsson;Y. Guan
Significance Farnesoid X (FXR) receptor is a ligand-activated transcription factor that regulates bile acid, lipid and glucose metabolism. It can be activated by endogenous bile acids, including chenodeoxycholic acid. This study uncovers a unique role for FXR to regulate urine volume independently of antidiuretic hormone and identifies aquaporin 2 as a direct target gene of FXR in renal collecting ducts. These findings provide a unique mechanism involved in the regulation of urinary concentrating process. The present study may also help understand the pathogenesis of hepatorenal syndrome, a state with increased circulating bile acid levels and impaired renal function. The farnesoid X receptor (FXR) is a ligand-activated transcription factor belonging to the nuclear receptor superfamily. FXR is mainly expressed in liver and small intestine, where it plays an important role in bile acid, lipid, and glucose metabolism. The kidney also has a high FXR expression level, with its physiological function unknown. Here we demonstrate that FXR is ubiquitously distributed in renal tubules. FXR agonist treatment significantly lowered urine volume and increased urine osmolality, whereas FXR knockout mice exhibited an impaired urine concentrating ability, which led to a polyuria phenotype. We further found that treatment of C57BL/6 mice with chenodeoxycholic acid, an FXR endogenous ligand, significantly up-regulated renal aquaporin 2 (AQP2) expression, whereas FXR gene deficiency markedly reduced AQP2 expression levels in the kidney. In vitro studies showed that the AQP2 gene promoter contained a putative FXR response element site, which can be bound and activated by FXR, resulting in a significant increase of AQP2 transcription in cultured primary inner medullary collecting duct cells. In conclusion, the present study demonstrates that FXR plays a critical role in the regulation of urine volume, and its activation increases urinary concentrating capacity mainly via up-regulating its target gene AQP2 expression in the collecting ducts.
