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Kidney Week

Abstract: TH-PO097

MUTYH, a DNA Repair Enzyme, Protects Against Cisplatin-Induced AKI

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Zhang, Aihua, Children's Hospital of Nanjing Medical University, Nanjing, China
  • Yang, Yunwen, Children's Hospital of Nanjing Medical University, Nanjing, China
  • Zhang, Yue, Children's Hospital of Nanjing Medical University, Nanjing, China
  • Ding, Guixia, Children's Hospital of Nanjing Medical University, Nanjing, China
  • Huang, Songming, Children's Hospital of Nanjing Medical University, Nanjing, China
  • Jia, Zhanjun, Children's Hospital of Nanjing Medical University, Nanjing, China
Background

MutY homolog (MUTYH) is a DNA Repair Enzyme and plays a key role in base excision repair (BER) for mitochondria (type I MUTYH works for mitochondrial DNA repair) and nuclear genome (type II MUTYH works for nuclear DNA repair). The current study aimed to evaluate the role of MUTYH in cisplatin-induced acute kidney injury.

Methods

In Vivo, Male MUTYH-/- mice and littermate WT controls were treated with cisplatin (20 mg/kg, ip). In vitro, mouse proximal tubular cells (mPTCs) with stable overexpression of MUTYH I or II were treated with cisplatin (5 mg/mL).

Results

In WT mice, cisplatin strikingly reduced MUTYH protein expression by 40%. MUTYH deficiency aggravated cisplatin-induced renal dysfunction (Scr: MUTYH -/- 112.5±18.8 vs. WT 33.60±9.14 mM, p<0.01; BUN: MUTYH -/- 67.65±4.0 vs. WT 37.83±4.99 mM p<0.01). Meanwhile, the renal tubular injury markers of KIM-1 and NGAL in MUTYH -/- mice were also further enhance by 191% and 94.11%, respectively, as compared with the WT mice after cisplatin treatment. The levels of cleaved caspase-3 and the number of TUNEL-positive cells in the kidneys of cisplatin-treated MUTYH-/- mice were higher than those in the kidneys of WT mice, showing the aggravated apoptotic response. Moreover, MUTYH deficiency resulted in the accumulation of 8-OHdG (indicating more severe DNA damage) and the aggravation of mitochondrial dysfunction. In vitro, Overexpression of type II MUTYH strikingly ameliorated cell apoptosis and oxidative stress induced by cisplatin, while MUTYH I overexpression showed a marginal role against cisplatin-induced cell injury.

Conclusion

MUTYH II but not MUTYH I played a significant role in protecting against cisplatin-induced acute kidney injury. Targeting type II MUTYH could be a promising strategy for the treatment of AKI.