Farnesoid X receptor is essential for the survival of renal medullary collecting duct cells under hypertonic stress

Sujuan Xu, Shizheng Huang, Zhilin Luan, Tingyue Chen, Yuanyi Wei, Miaomiao Xing, Yaqing Li, Chunxiu Du, Bing Wang, Feng Zheng, Nanping Wang, Youfei Guan, Jan Åke Gustafsson, Xiaoyan Zhang

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Hypertonicity in renal medulla is critical for the kidney to produce concentrated urine. Renal medullary cells have to survive high medullary osmolarity during antidiuresis. Previous study reported that farnesoid X receptor (FXR), a nuclear receptor transcription factor activated by endogenous bile acids, increases urine concentrating ability by up-regulating aquaporin 2 expression in medullary collecting duct cells (MCDs). However, whether FXR is also involved in the maintenance of cell survival of MCDs under dehydration condition and hypertonic stress remains largely unknown. In the present study, we demonstrate that 24-hours water restriction selectively up-regulated renal medullary expression of FXR with little MCD apoptosis in wild-type mice. In contrast, water deprivation caused a massive apoptosis of MCDs in both global FXR gene-deficient mice and collecting duct-specific FXR knockout mice. In vitro studies showed that hypertonicity significantly increased FXR and tonicity response enhancer binding protein (TonEBP) expression in mIMCD3 cell line and primary cultured MCDs. Activation and overexpression of FXR markedly increased cell viability and decreased cell apoptosis under hyperosmotic conditions. In addition, FXR can increase gene expression and nuclear translocation of TonEBP. We conclude that FXR protects MCDs from hypertonicity-induced cell injury very likely via increasing TonEBP expression and nuclear translocation. This study provides insights into the molecular mechanism by which FXR enhances urine concentration via maintaining cell viability of MCDs under hyperosmotic condition.

Original languageEnglish (US)
Pages (from-to)5600-5605
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number21
DOIs
StatePublished - May 22 2018

Keywords

  • Bile acid receptor
  • Cell viability
  • Hypertonicity
  • NFAT5
  • Osmoprotection

ASJC Scopus subject areas

  • General

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