Abstract: FR-PO345

Lactic Acid Production from Glycolysis Activates TGF-b/Smad Signaling Pathway in Tubular Epithelial Cells Engaged in the Development of Renal Fibrosis

Session Information

Category: Chronic Kidney Disease (Non-Dialysis)

  • 308 CKD: Mechanisms of Tubulointerstitial Fibrosis

Authors

  • Xu, Jing, Nanjing Medical University, Nanjing, China
  • Shen, Yan, Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, Nanjing, China
  • Jiang, Lei, Second Affliliated Hospital, Nanjing Medical University, Nanjing, China
  • Yang, Junwei, Second Affiliated Hospital, Nanjing Medical University, Nanjing, China
Background

Renal proximal tubule is susceptible to hypoxic injury, because of the reliance on aerobic oxidative metabolism. Dysfunctional mitochondria participate the progression of chronic renal disease. In this paper, we investigate the profile of the energy metabolism of the proximal epithelial cell in fibrotic kidney, and evaluate the role of anaerobic metabolism in renal fibrosis.

Methods

2-deoxyglucose (2-DG) was administered at a dose of 20mg/kg or 100mg/kg and Shikonin was oral performed at a dose of 1 or 5 mg/kg before unilateral ureter obstruction (UUO) surgery and administered for successive7 days. Human Recombinant TGF-β1 (5 ng/ml) and lactic acid (10mmol/L) were added to the serum-free medium for indicated time periods and concentration. 2-DG (0.2 or 1mM), dichloroacetic acid (DCA,2mM), BroPA (5nM) and oxamate (100nM) were added to the serum-free medium 30 minutes for indicated time periods and concentration before TGF-β1 treatment.

Results

The protein expression of key enzymes of glycolysis were markedly increased in a time depended in UUO induced renal interstitial fibrosis mice model. There was a similar result in primary renal tubular epithelial cells after disposed with TGF-β1.In addition, the fibrotic matrix was reduced and marks of collagen fibrils such as α-smooth muscle actin (α-SMA), fibronectin (FN) were down-regulated after mice or primary renal tubular epithelial cells (PTC) dealed with inhibitors of glycolytic pathway. At the same time, we found the expression of TGF-β1 receptor and p-smad3 were decreased. In the meantime, lactic acid, the production of glycolysis pathway, was involve in the activation of TGF-β1-smad pathway and changed renal tubular cells phenotype and contributed to the development of renal interstitial fibrosis.

Conclusion

Altered glucose metabolism of tubular epithelial cells is a hallmarks of renal fibrosis. Inhibition of aerobic glycolysis is effective to suppress renal fibrosis. Lactic acid production from glycolysis could further active TGFβ1/smad signaling and aggravate renal fibrosis.

Funding

  • Government Support - Non-U.S.