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DNase I-Like Endonuclease in Rat Kidney Cortex That Is Activated during Ischemia/Reperfusion Injury

Alexei G. Basnakian^*, Norishi Ueda^*, Gur P. Kaushal^*, Marina V. Mikhailova^* and Sudhir V. Shah^*

*University of Arkansas for Medical Sciences, Little Rock, Arkansas, and Central Arkansas Veterans Healthcare System, Little Rock, Arkansas.

Correspondence to Dr. Alexei G. Basnakian, Department of Internal Medicine, Division of Nephrology, University of Arkansas for Medical Sciences, 4301 W. Markham St., Slot 501, Little Rock, AR 72205. Phone: 501-257-1000, ext. 54861; Fax: 501-257-5827; E-mail: basnakianalexeig{at}uams.edu

ABSTRACT. Ischemia/reperfusion is known to result in DNA fragmentation and cell death in kidney tubular epithelium, but the endonucleases responsible for this DNA damage have not been identified. DNA substrate gel analysis of extracts from normal rat kidney cortex revealed the presence of a DNase with an apparent molecular mass of 30 to 34 kD. This enzyme is not a dimer of the previously described nuclear 15-kD endonuclease in kidney cells. Partially purified DNase exhibited characteristics similar to those of rat DNase I. The DNase was able to digest circular DNA (endonuclease), required both Ca²⁺ and Mg²⁺ ions, and was inhibited by Zn²⁺ and by aurintricarboxylic acid; it was not inhibited by G-actin. Rat kidneys were subjected to 40 min of ischemia, followed by 0, 1, 4, 16, or 48 h of reperfusion. The activity of the DNase in cytosolic and nuclear extracts, the 200-bp ladder-generating activity, and 3'OH strand breaks in nuclear DNA were simultaneously increased after ischemia, during the first hours of reperfusion. Oxidative DNA damage, measured as 8-hydroxydeoxyguanosine content, did not coincide with endonuclease-generated DNA breaks. Oxidative DNA damage was increased during ischemia and gradually decreased during reperfusion. Phosphorothioated DNase I antisense oligodeoxynucleotide introduced into cultured NRK-52E rat kidney epithelial cells inhibited DNA fragmentation and attenuated cell death induced by hypoxia/reoxygenation in vitro. The data indicate that the DNase I-like endonuclease may contribute to DNA fragmentation in reperfused rat kidneys.

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