Kidney Week

Abstract: SA-PO833

TSC1 Mediated Metabolic Switch to Glycolysis in Tubular Epithelial Cell Accelerates Renal Interstitial 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

• Cao, Hongdi, Second Affliliated Hospital, Nanjing Medical University, Nanjing, China

Hongdi Cao,

• Jiang, Lei, Second Affliliated Hospital, Nanjing Medical University, Nanjing, China

Lei Jiang,

• Yang, Junwei, Second Affliliated Hospital, Nanjing Medical University, Nanjing, China

Junwei Yang,

Background

Renal interstitial fibrosis is a key factor in the progression of chronic kidney disease (CKD). Energy reprogram to glycolysis is closely related to the development of CKD. As an important negative regulatory factor of mTORC1 signal，tuberous sclerosis complex 1 (Tsc1) is also the key regulatory point of glycolysis. In this study, we investigated whether Tsc1 could mediate the progress of renal interstitial fibrosis by regulating glycolysis in proximal tubular epithelial cells.

Methods

In vitro and in vivo models of renal interstitial fibrosis were established. The changes of Tsc1 in the progress of renal interstitial fibrosis and the relationship of glycolysis and Tsc1 were analyzed. The glycolysis level and degree of fibrosis in kidneys between proximal tubular epithelial cells-Tsc1 specific knockout mice(Tsc1^ptKO mice) and control mice were compared to explore the role Tsc1 in renal interstitial fibrosis.

Results

In TGF-β1 induced tubular epithelial cell phenotype transformation and UUO models, Tsc1 in tubular epithelial cells was reduced markedly. In Tsc1^ptKO mice, mTORC1 signal was activated and showed the significant feature of renal interstitial fibrosis. Mitochondrial damage and enhanced glycolysis were observed in tubular epithelial cell phenotype transformation, UUO mice and Tsc1^ptKO mice. Inhibiting glycolysis of proximal tubular cells induced by Tsc1 downregulation with 2-DG, the fibrotic phenotypic changes induced by Tsc1 decline were improved. The renal fibrotic degree was also alleviated by inhibiting the glycolysis of Tsc1^ptKO mice with 2-DG.

Conclusion

Tsc1 could mediate the progress of renal interstitial fibrosis by regulating glycolysis in proximal tubular epithelial cells. It might be helpful to provide theoretical basis for design of new therapeutic strategies of CKD.

Funding

• Government Support - Non-U.S.