Abstract: SA-PO311

Hypoxia-Inducible Factors-1α Driving a Metabolic Shift in Tubular Epithelial Cells Promotes Renal Fibrosis

Session Information

Category: Chronic Kidney Disease (Non-Dialysis)

  • 308 CKD: Mechanisms of Tubulointerstitial Fibrosis

Authors

  • Yuan, Qi, Nanjing Medical University, Jiangsu Nanjing, China
  • Yang, Junwei, Second Affiliated Hospital, Nanjing Medical University, Nanjing, China
Background

Hypoxia promotes fibrosis in various renal disease models. Hypoxia-inducible factor 1 (HIF-1), a transcriptional factor, is a master regulator of gene expressions under hypoxic conditions. Fatty acids are used to fuel oxidative phosphorylation (OXPHOS) to produce ATP in normal tubular epithelial cells. Hypoxia can drive glycolysis, as an oxygen deficit results in limited OXPHOS. Recent studies have established that besides glycolysis, several aspects of lipid metabolism including lipid droplets and β-oxidation play key roles in adaptation to low oxygen conditions. Therefore, we hypothesize that the HIF pathway may provide a switch through which metabolic phenotypes can be amended during the process of renal fibrosis.

Methods

Western blot and qPCR analysis were performed to examine the levels of lipid catabolism enzymes, glycolytic enzymes and HIF-1α in folic acid (FA) induced renal fibrotic mice. Then, FA mice were administered with control or dinitrophenol (DNP), which causes kidney hypoxia and activates HIF-1α, to determine whether HIF-1α affects metabolic switch. Further mechanism was searched in tubular epithelial cells in vitro.

Results

We identified significant lipid accumulation and higher expression of glycolytic enzymes accompanied with up-regulated HIF-1α in renal tissues of FA mice. DNP treatment decreased fatty acid oxidation and increased glycolysis, which served to maintain sustained ATP and promote fibroblast proliferation and ECM production in mice kidney. In tubular epithelial cells, TGF-βaccumulated higher amount of lipids through a combination of metabolic alterations including fatty acid uptake, decreased fatty acid oxidation, and activated glycolysis enzymes, while increased the markers of collagen fibrils. Transfection with siRNA to HIF-1α reversed the effect in vitro.

Conclusion

It can be concluded that HIF-1α plays a major role in the metabolic reprogramming of renal fibrosis. Targeting the HIF pathway may provide novel therapeutic approach of kidney fibrosis.

Funding

  • Government Support - Non-U.S.