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Abstract: FR-PO356

Empagliflozin Rescues the Loss of Mitochondrial Mass via ERRα in Proximal Tubular Epithelial Cells from db/db Mice

Session Information

Category: Diabetic Kidney Disease

  • 701 Diabetic Kidney Disease: Basic

Authors

  • Yang, Keju, 1. Renmin Hospital of Wuhan University, Wuhan, Hubei, China
  • Hu, Hongtu, 1. Renmin Hospital of Wuhan University, Wuhan, Hubei, China
  • Ding, Guohua, 1. Renmin Hospital of Wuhan University, Wuhan, Hubei, China
  • Liang, Wei, 1. Renmin Hospital of Wuhan University, Wuhan, Hubei, China

Group or Team Name

  • Division of Nephrology, Renmin Hospital of Wuhan University, Hubei, China.
Background

It is known that mitochondrial dysfunction of proximal tubular epithelial cells(PTECs) contributes to the pathogenesis of diabetic nephropathy. However, the ultrastructural changes of PTEC mitochondria in diabetic kidneys remain unclear. Empagliflozin(EMPA) protects the diabetic kidney via SGLT2 located only on PTECs. ERRα is highly expressed in PTECs and associated with mitochondrial biogenesis. The present study aimed to investigate the role of ERRα on mitochondrial mass in diabetic tubular injury and the mechanism of the protective effects of EMPA.

Methods

Transmission electron microscopy (TEM) was used to identify ultrastructural changes in the mitochondria of PTECs from diabetic mice and RNA sequences of isolated renal tubules was performed to identify the DEGs related to mitochondria and ERRα. The expression of ERRα was also evaluated by immunohistochemistry(IHC) and Western blot(Wb). EMPA was then administrated to db/db mice for 12 weeks and the mitochondria was assessed by TEM and the expression of ERRα was evaluated by Wb,RT-qPCR and IHC. Wb was also used to assess the expression of Fis1 and PGC1α. In HK-2 cells, High glucose(HG) or ERRα siRNA or pcDNA-ERRα or EMPA were used to modify the expression of ERRα.The mass and function of mitochondria were evaluated by Mitotracker Red and JC-1 in corresponding culture conditions.

Results

PTECs presented less mitochondrial mass and swelling mitochondria with more mitochondrial cristae fracture in 16-week-old db/db mice. RNA-sequences of isolated renal tubules from db/db mice revealed that 110 downregulated genes were related to mitochondrial function or mitochondrial energy metabolism. ERRα is among the genes with prominent changes. The downregulation of ERRα in diabetic kidney was further evaluated by Wb and IHC. In HG exposed HK-2 cells, the expression of ERRα was decreased and the mitochondrial mass and membrane potential(MMP) were inhibited. ERRα gene silencing decreased mitochondrial mass and MMP while ERRα overexpression or EMPA rescued HG-induced loss of mitochondrial mass in HK-2cells. In vivo, EMPA alleviated ultrastructural changes of PTECs and the downregulation of ERRα from db/db mice.

Conclusion

Decreased ERRα contributes to the loss of mitochondrial mass of PTECs in the early stage of diabetes and is a target of EMPA to prevent the progression of diabetes on kidney injury.

Funding

  • Government Support – Non-U.S.