Kidney Week

Abstract: SA-PO824

Activation of FXR Regulates Kidney Autophagy for Suppressing Renal Fibrosis

Session Information

• Molecular Mechanisms of CKD - III
  October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 1903 CKD (Non-Dialysis): Mechanisms

Authors

• Kim, Donghyun, Chonnam National University Hospital, Gwangju, Korea (the Republic of)

Donghyun Kim,

• Choi, Hoon In, Chonnam National University Medical School, Gwangju, Korea (the Republic of)

Hoon In Choi,

• Park, Jung Sun, chonnam national university, Gwang Ju, Korea (the Republic of)

Jung Sun Park,

• Bae, Eun Hui, Chonnam National University Hospital, Gwangju, Korea (the Republic of)

Eun Hui Bae,

• Ma, Seong Kwon, Chonnam National University Medical School, Gwangju, Korea (the Republic of)

Seong Kwon Ma,

• Kim, Soo Wan, Chonnam National University Medical School, Gwangju, Korea (the Republic of)

Soo Wan Kim,

Background

Autophagy is an evolutionarily conserved catabolic process that removes damaged organelles and maintains cellular energy homeostasis. Acute regulation by nutrient-sensing of autophagy and long-term transcriptional regulation by nuclear hormone receptor farnesoid X receptor (FXR) is well known. Also, kidney autophagy regulates TGFβ expression and suppresses kidney fibrosis. However, the functional role of FXR on TGFβ-induced kidney autophagy is relatively unknown.

Methods

Expression levels of LC3 protein and autophagy related genes were measured on treatment with TGFβ and FXR agonists, GW4064, CDCA, and INT-747, in human proximal tubule cells (HK2 cells). Also, we tested expression levels of autophagy related proteins and genes in unilateral ureteral obstruction mice model. The LC3 Puncta formation was monitored by fluorescence microscopy. Expression levels of protein and autophagy related genes were measured on down-regulation of FXR by siRNA in HK2 cells or FXR knock-out mice.

Results

Treatment with TGFβ (5 ng/ml) in HK2 cells resulted in an increase in the level of LC3 protein and autophagy related genes, along with an increase in fibrosis markers. Activation of FXR by agonists in TGFβ-induced HK2 cells regulates LC3 I and II expression levels. Autophagy related genes were decreased in FXR agonists treated HK2 cells. Also, autophagic flux was further increased on co-treatment with GW4064 and TGFβ in HK2 cells. Autophagy related genes has no GW4064 effects on down-regulation of FXR by siRNA in HK2 cells. Protein levels of LC3 and fibrosis markers were increased in FXR-KO UUO mice model compared to those of WT UUO mice model.

Conclusion

These data reveal a functional role of FXR for kidney autophagy regulator in TGFβ-induced HK2 cells and suggest that FXR may play an important role in the suppression of renal fibrosis through kidney autophagy.

Funding

• Government Support - Non-U.S.