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Abstract: TH-PO203

PGC1α Modulates Mitochondrial Homeostasis in Tubular Cells of Diabetic Kidney Disease

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Ye, Siyang, Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
  • Li, Bin, Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
  • Fan, Yuting, Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
  • Lin, Yi, Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
  • Li, Suchun, Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
  • Peng, Huajing, Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
  • Diao, Hui, Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
  • Chen, Wei, Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
Background

Tubular injury and dysregulated mitochondrial dynamics play pivotal roles in the pathogenesis of diabetic kidney disease (DKD). However, the potential mechanism by which mitochondrial dysfunction-initiated tubulopathy triggers intrarenal signaling and mediates DKD progression remains elusive. Our current study aims to investigate the effect of PGC1α-modulated mitochondrial homeostasis on kidney tubular cells of DKD and to explore the underlying mechanisms.

Methods

Human renal proximal tubule epithelial cells (HK-2) were cultured in the presence of palmitic acid (PA, 500 μM) plus high glucose (HG, 40 mM) to imitate the diabetic microenvironment. PGC1α was overexpressed in cultured HK-2 cells through plasmid transfection to perform functional experiments. Mitochondrial status and the related molecular patterns were assessed using multiple standard molecular biology techniques.

Results

The transcript and protein expression profile of PGC1α were significantly inhibited when HK-2 cells were exposed to PA plus HG. In parallel, transcription factor A (TFAM), the important mediator of mitochondrial biogenesis, as well as PTEN-induced kinase 1 (PINK1) and Parkin (parkin RBR E3 ubiquitin protein ligase), the key regulators of mitophagy, were significantly suppressed at both transcriptional and protein level, which resulted in obviously blunted mitochondrial biogenesis and mitophagy, as evidenced by reduced mitochondrial content including mitochondrial marker TOM20 (translocase of outer mitochondrial membrane 20), mitochondrial volume and mitochondrial DNA. Moreover, mitochondrial dysfunction led to dramatically elevated proinflammatory mediators including IL6, IL8, and ICAM1 (intercellular adhesion molecule 1) in cultured HK-2 cells. More importantly, PA plus HG-initiated perturbation of intracellular mitochondrial dynamics and inflammation were prevented by overexpression of PGC1α in cultured HK-2 cells.

Conclusion

Findings from our study support an important role for PGC1α in preventing DKD-induced mitochondrial dysfunction in tubular cells via maintaining the activation of TFAM and PINK1/Parkin signaling. Functionally, this enables the mitochondrial homeostasis and diminishes the consequent inflammation in the microenvironment of DKD. Means of targeting PGC1α-regulated mitochondrial homeostasis represents a promising target for the treatment of DKD.

Funding

  • Government Support – Non-U.S.