Background: Uncoupling protein 1 (UCP1) is predominantly found in brown adipose tissue mitochondria, and mediates energy dissipation to generate heat rather than ATP via functional mitochondrial uncoupling. However, little is known about its expression and function in kidney. Methods: We carried out a mRNA microarray analysis in mice kidneys with ischemia reperfusion (IR) injury. The most dramatically downregulated gene UCP1 after IR was identified, and its role in generation of mitochondrial reactive oxygen species (ROS) and oxidative stress injury was assessed both in vitro and in vivo. Genetic deletion of UCP1 was used to investigate the effects of UCP1 on ischemia or cisplatinindued acute kidney injury (AKI) in mice. Findings: UCP1 was located in renal tubular epithelial cells in kidney and downregulated in a timedependent manner during renal IR. Deletion of UCP1 increased oxidative stress in kidneys and aggravated ischemia or cisplatin induced AKI in mice.Viral-based overexpression of UCP1 reduced mitochondrial ROS generation and apoptosis in hypoxia-treated tubular epithelial cells. Furthermore, UCP1 expression was regulated by peroxisome proliferator-activator receptor (PPAR) γ in kidneys during renal IR. Overexpression of PPAR-γ resembled UCP1-overexpression phenotype in vitro. Treatment with PPAR-γ agonist could induce UCP1 upregulation and provide protective effect against renal IR injury in UCP1 + / + mice, but not in UCP1 −/ − mice. Interpretation: UCP1 protects against AKI likely by suppressing oxidative stress, and activation of UCP1 represents a potential therapeutic strategy for AKI.

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.

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