Abstract: SA-PO195

Podocyte De-Differentiation Repatterns Energy Metabolism and Promotes Cellular Crescent Formation

Session Information

  • Glomerular: Cell Biology
    November 04, 2017 | Location: Hall H, Morial Convention Center
    Abstract Time: 10:00 AM - 10:00 AM

Category: Glomerular

  • 1003 Glomerular: Cell Biology

Authors

  • Miao, Jiao, Center for Kidney Disease, Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
  • Sun, Qi, Second Affiliated Hospital, Nanjing Medical University, Nanjing, China
  • Yang, Junwei, Second Affiliated Hospital, Nanjing Medical University, Nanjing, China
Background

The role of podocytes in human crescentic glomerulonephritis (GN) has been underestimated. This may be due to the confounding fact that “dysregulated” podocytes are able to proliferate, lose their markers, and undergo de-differentiation. Specific deletion of Tsc1 in podocytes led to spontaneous cellular or mixed cellular and fibrous crescents at 12 wk of age. These cellular crescents were immunostaining positive for WT-1 and Ki-67, suggesting that podocytes proceed profound phenotype changing in this model. This study is to investigate the mechanism that governs podocyte de-differentiation. Here we demonstrated that a switch of metabolism from oxidative phosphorylation to aerobic glycolysis was the primary feature during podocyte de-differentiation and also might be the initial step to promote proliferating.

Methods

Renal biopsies from patients with anti-GBM disease, lupus GN and IgA nephropathy were studied by immunofluorescence for WT-1 for podocyte identification and Ki-67 for cell cycle assessment. The de-differentiated podocyte undergoing proliferation was assessed by flow cytometry and fluorescent. Western blot and quantitative real-time PCR were performed to examine the expression level of glycolysis related enzymes. Meanwhile, podocyte-specific Tsc1 knockout mice were generated as a model for crescentic GN.

Results

Both gene and protein assay showed that the expression of glycolysis enzymes were upregulated in Tsc1KO mouse kidneys or in TGFβ1-treated podocytes. Aerobic glycolysis flux, indicated by glucose uptake and lactate production, was increased in TGFβ1-treated podocyte and positively correlated with cell de-differentiation and proliferation. Furthermore, continuously administrating 2-DG starting at 4 wk of age for 8 wk alleviateed crescents formation as well as the induction of p-S6, HIF1a, and PFK in the glomeruli from the Tsc1-knockouts.

Conclusion

Our findings demonstrate the critical role of aerobic glycolysis in podocyte de-differentation and proliferation and provide the treatment with aerobic glycolysis inhibitors as a potential anti-crescentic GN strategy.

Funding

  • Government Support - Non-U.S.