Abstract: SA-PO290

Activated Farnesoid X Receptor by GW4064 Protects against Renal Fibrosis through Regulation of Hippo Pathway

Session Information

Category: Cell Biology

  • 204 Extracellular Matrix Biology, Fibrosis, Cell Adhesion

Authors

  • Kim, Donghyun, Chonnam National University Hospital, Gwangju, Korea (the Republic of)
  • Bae, Eun Hui, Chonnam National University Hospital, Gwangju, Korea (the Republic of)
  • Ma, Seong Kwon, Chonnam National University Medical School, Gwangju, Korea (the Republic of)
  • Kim, Soo Wan, Chonnam National University Medical School, Gwangju, Korea (the Republic of)
Background

Renal fibrosis is the common pathway of chronic kidney disease progression. transforming growth factor-β(TGF-β) induced SMAD2/3 is a critical event in progressive chronic kidney disease. However, the role of non-SMAD signaling in fibrotic progress and its underlying molecular mechanisms remain unexplored. The nuclear receptor farnesoid X receptor (FXR), a ligand-activated transcriptional factor, may play a pivotal role in renal fibrosis.

Methods

We tested whether activated-FXR by GW4064 protects against renal fibrosis through non-SMAD signaling. To explore anti-fibrotic effects of FXR, we investigated the effects of GW4064 in TGF-β induced renal fibrosis in human proximal tubular epithelial (HK-2) cells. We also examined the phosphorylation level of epidermal growth factor receptor (EGFR), Src kinase and Hippo pathway to identify the anti-fibrotic signals. To explore the anti-fibrotic effects of FXR agonist in the kidney of unilateral ureteral obstruction (UUO) mouse model, we treated with vehicle or GW4064 (30mg/kg) for 5 days, and checked the fibrosis markers.

Results

TGF-β-induced Src kinase and EGFR phosphorylations were decreased by the treatment of FXR synthetic agonist GW4064, while those phosphorylations were not altered by the treatment of chenodoxycholic acid (CDCA), FXR agonist. TGF-β-induced fibronectin, connective tissue growth factor and α-smooth muscle actin expressions were markedly decreased by GW4064 treatment. Phosphorylations of yes-associated protein (YAP), Mst1/2, and Lats1 were increased by GW4064 treatment, which facilitates blocked YAP nuclear accumulation and protects against renal fibrosis. The in vivo experiments showed that FXR agonist GW4064 protected against renal fibrosis in UUO mice.

Conclusion

These results suggested that activated nuclear receptor FXR by GW4064 has anti-fibrotic effects through regulation of Hippo pathway by inhibition of Src kinase phosphorylation. FXR-Src-Hippo pathway may be a novel target for the treatment of renal fibrosis.

Funding

  • Government Support - Non-U.S.