Abstract: TH-OR020

MicroRNA-709 Mediates Acute Tubular Injury by Negatively Regulating the TFAM/Mitochondria Axis

Session Information

Category: Acute Kidney Injury

  • 001 AKI: Basic

Authors

  • Zhang, Aihua, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
  • Guo, Yan, Nanjing Medical University, Nanjing, China
  • Zhang, Yue, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
  • Huang, Songming, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
  • Jia, Zhanjun, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
Background

Mitochondrial dysfunction (MtD) plays important roles in the pathogenesis of acute kidney injury (AKI), whereas therapeutic approaches to improve mitochondrial function are still limited. In the present study, we investigated the pathogenic role of miR-709 in mediating mitochondrial impairment and tubular cell death in AKI.

Methods

We used cisplatin-induced AKI mouse model and renal tubular cells to investigate the role of miR-709 in AKI, as well as the mechanisms. The mitochondrial function was determined by the examination of mitochondrial DNA copy number, mitochondrial membrane potential, mitochondrial ROS production, oxygen consumption and the expressions of mitochondrial proteins.

Results

In cisplatin-treated mice, renal miR-709 was significantly upregulated by more than 2 folds. In proximal tubular cells (PTCs), cisplatin led to 6-fold increase of miR-709. Notably, overexpression of miR-709 in mouse PTCs significantly induced MtD and cell apoptosis (>50%), whereas inhibition of miR-709 ameliorated cisplatin-induced MtD and cell apoptosis (about 50%). Further analyses showed that TFAM (mitochondrial transcriptional factor A) is a target gene of miR-709 and that genetic restoration of TFAM blocked the MtD and cell injury induced by cisplatin or miR-709 overexpression. More importantly, miR-709 antagonism with a miR-709 antagomir dramatically attenuated cisplatin-induced kidney injury and MtD in mice. Finally, we verified the overexpression of miR-709 in renal PTCs of 21 patients with AKI of various etiologies (ischemia, nephrotoxins et al), and found a close correlation between the expression of miR-709 and the severity of kidney injury.

Conclusion

These results suggest that miR-709 plays an important role in mediating cisplatin-induced AKI via negative regulation of TFAM and subsequent MtD.