Abstract: FR-PO179

SIRT1/P53/Drp1-Dependent Mitochondrial Fission Mediates Aldosterone-Induced Podocyte Injury and Mitochondrial Dysfunction

Session Information

  • Mitochondriacs and More
    November 03, 2017 | Location: Hall H, Morial Convention Center
    Abstract Time: 10:00 AM - 10:00 AM

Category: Glomerular

  • 1002 Glomerular: Basic/Experimental Pathology

Authors

  • Yuan, Yanggang, Nanjing Medical University, Nanjing, China
  • Zhang, Aihua, Nanjing Medical University, Nanjing, China
  • Xing, Changying, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
Background

Mitochondrial dysfunction is increasingly recognized as an important factor in glomerular diseases. Previous study showed that mitochondrial fission contributed mitochondrial dysfunction. However, the mechanism of mitochondrial fission on mitochondrial dysfunction in aldosterone-induced podocyte injury remains ambiguous. This study aimed to investigate the pathogenic effect of mitochondrial fission both in vivo and in vitro.

Methods

Aldosterone-infused mice were implanted subcutaneously with 14-day-release pellets containing aldosterone. Mitochondrial fission inhibitor mdivi-1 was given by peritoneal injection. The expression of mitochondrial fission protein Drp1 (dynamin-related protein 1) was determined by western blotting and immunofluorescence. Podocyte injury was measured by nephrin expression and labelled by TUNEL assay. In vitro, podocytes were treated with aldosterone at the concentration of 0, 25, 50, 100 nmol/L. The expressions of Drp1, p53 and SIRT1 were examined by real-time PCR and western blot. Then podocytes were transfected with Drp1 siRNA, p53 siRNA and SIRT1 plasmid, respectively. After aldosterone treatment, podocyte injury, mitochondrial morphology and mitochondrial function were detected.

Results

In an animal model of aldosterone-induced nephropathy, inhibition of Drp1 suppressed aldosterone-induced podocyte injury. In cultured podocytes, aldosterone dose-dependently induced Drp1 expression. Knockdown of Drp1 inhibited aldosterone-induced mitochondrial fission, mitochondrial dysfunction and podocyte apoptosis. In addition, aldosterone dose-dependently induced p53 expression. Knockdown of p53 inhibited aldosterone-induced Drp1 expression, mitochondrial dysfunction and podocyte apoptosis. Furthermore, aldosterone dose-dependently decreased SIRT1 expression. SIRT1 overexpression blocked aldosterone-induced p53 and Drp1 expression, mitochondrial dysfunction and podocyte injury.

Conclusion

These findings implicated that aldosterone-induced mitochondrial dysfunction and podocyte injury mediated by SIRT1/p53/Drp1-dependent mitochondrial fission, which may provide opportunities for therapeutic intervention for podocyte injury.

Funding

  • Government Support - Non-U.S.