Abstract: SA-PO313

Autophagy Is Induced via HIF-1 to Facilitate Renal Interstitial Fibrosis during Unilateral Ureteral Obstruction in Mice and Hypoxia in Tubular Cells

Session Information

Category: Chronic Kidney Disease (Non-Dialysis)

  • 308 CKD: Mechanisms of Tubulointerstitial Fibrosis

Authors

  • Liu, Jing, The Second Xiangya Hospital,Central South University, Changsha, China
  • Livingston, Man J., Augusta University Medical College of Georgia, Augusta, Georgia, United States
  • Wei, Qingqing, Augusta University Medical College of Georgia, Augusta, Georgia, United States
  • Dong, Zheng, Augusta University Medical College of Georgia, Augusta, United States
Background

Autophagy, a fundamental cellular catabolic process, has recently been implicated in renal fibrosis. However, it is unclear how autophagy is activated under this condition. Hypoxia-inducible factors (HIF) are master regulators of hypoxia responsive genes and may contribute to renal fibrosis. Whether HIF is involved in autophagy activation during renal fibrosis is largely unknown.

Methods

In vivo, renal fibrosis was induced by unilateral urethral obstruction in mice. In vitro, renal proximal tubular cells were exposed to hypoxia to induce fibrotic changes. YC-1 was used to inhibit HIF pharmacologically. Kidney proximal tubule-specific HIF-1 knockout (PT-HIF-1 KO) mice were also examined.

Results

UUO induced HIF-1 and autophagy, which was accompanied by renal interstitial fibrosis. Pharmacological inhibition of HIF with YC-1 attenuated autophagy activation and renal interstitial fibrosis during UUO. Moreover, compared with wild-type mice, PT-HIF-1 KO mice showed significantly lower autophagy during UUO. These mice also had lower levels of renal fibrosis as shown by the decreased expression of fibronectin, collagen I, α-SMA and vimentin. In cultured proximal tubular cells, hypoxia induced HIF-1, autophagy, and the accumulation of fibronectin, which were suppressed by the HIF inhibitor YC-1. In addition, knockdown HIF-1 in these cells attenuated autophagy activation and fibronectin accumulation during hypoxia exposure.

Conclusion

The results suggest that in renal fibrosis, HIF-1 may activate autophagy in renal tubular cells to facilitate the development of renal interstitial fibrosis.

Funding

  • NIDDK Support