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Kidney Week

Abstract: SA-PO578

Mitigation of AKI in Mice Using DNase I Inhibitor

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Fite, Todd, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States
  • Savenka, Alena, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States
  • Basnakian, Alexei G., University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States
Background

Our previous studies showed that genetic inactivation of the most active kidney apoptotic endonuclease, DNase I, was partially protective against tubular epithelial cell death induced by hypoxia-reoxygenation or cisplatin. Our recent discovery of the first pharmaceutically meaningful DNase I inhibitor, IG-17, provides an opportunity for the development of first anti-DNase drug mitigating acute kidney injury (AKI).

Methods

In vitro experiments using kidney tubular epithelial NRK-52E cells showed that IG-17 was able to suppress DNase activity inside the cells, and provided partial protection against hypoxia-reoxygenation, cisplatin or hemin toxicity measured using LDH release assay and TUNEL.

Results

The absence of IG-17 toxicity in mice at 1, 5 or 25 mg/kg was shown by 14 blood plasma assays for organ function. AKI experiments were done in male and female mice subjected to bilateral kidney 50-min ischemia followed by 24-h reoxygenation, or injected with cisplatin (20 mg/kg, IP), or glycerol (50% solution, 8 ml/kg, IM). Kidney failure was measured by serum creatinine and BUN. Structural kidney damage was assessed by acute tubular necrosis and TUNEL. In all three in vivo models, SC or IP injections of IG-17 (5 mg/kg) were either partially (ischemia-reperfusion, cisplatin) or fully protective (glycerol).

Conclusion

The results of this study suggest that IG-17 has a promise as the first non-toxic anti-DNase agent for mitigation of AKI.

Funding

  • NIDDK Support