Farnesoid X Receptor Activation Protects Against Renal Fibrosis Via Modulation of Β-Catenin Signaling.

Objective: Activation of farnesoid X receptor (FXR), a bile acid nuclear receptor, may be implicated in the pathophysiology of diabetic nephropathy. We explored a possible role for FXR activation in preventing renal fibrosis in high fat diet (HFD)-fed mice.Methods: We investigated the effects of HFD on mouse kidney and renal tubular epithelial cells both in vivo and in vitro, and observed the changes of FXR and beta-catenin pathway. FXR agonist was also used to alleviate this HFD-induced effect, and the interaction between FXR and beta-catenin was further verified.Results: Mice were fed by a 60% kcal fat diet for 20 weeks developed the typical traits of metabolic syndrome with subsequent renal lipid accumulation and renal injury. Treatment with the FXR agonist CDCA or GW4064 decreased body weight, renal lipid accumulation, as well as renal injury. Moreover, renal beta-catenin signaling was activated and improved with FXR-agonist treatment in HFD-fed mice. To examine whether FXR affected beta-catenin signaling, and was involved in tubulo-interstitial fibrosis, we explored the FXR expression and function in ox-LDL induced-renal tubular injury. In rat proximal tubular epithelial cells (NRK-52E) stimulated by ox-LDL, FXR protein was decreased compared to control group, and phosphorylated (Ser675) beta-catenin was activated by ox-LDL in a dose- and time-dependent manner. Ox-LDL enhanced alpha-SMA and fibronectin expressions and reduced E-cadherin levels, whereas FXR agonism or FXR overexpression inhibited fibronectin and alpha-SMA expressions and restored E-cadherin. Moreover, FXR agonist treatment also decreased phosphorylated (Ser675) beta-catenin, nuclear translocation and beta-catenin-mediated transcription induced by ox-LDL in NRK-52E cells. We showed that FXR could bind with beta-catenin via the AF1 domain, and disrupt the assembly of the core beta-catenin/TCF4 complex.Conclusion: These experimental data suggest that FXR activation, via modulating beta-catenin signaling, may contribute to attenuating the development of lipid-mediated tubulo-interstitial fibrosis.