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Cu/Zn-Superoxide Dismutase Gene Attenuates Ischemia-Reperfusion Injury in the Rat Kidney

Ming Yin^*, Michael D. Wheeler^*, Henry D. Connor^*, Zhi Zhong^*, Hartwig Bunzendahl, Anna Dikalova^||, Richard J. Samulski, Robert Schoonhoven, Ronald P. Mason^||, James A. Swenberg and Ronald G. Thurman^*

Departments of *Pharmacology and Surgery, Gene Therapy Center, and Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, North Carolina; and ^||Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Science, Research Triangle Park, North Carolina.

Correspondence to Dr. Ronald G. Thurman, Department of Pharmacology, CB 7365, Mary Ellen Jones Building, University of North Carolina, Chapel Hill, NC 27599-7365. Phone: 919-966-4745; Fax: 919-966-1893; E-mail: thurman{at}med.unc.edu

ABSTRACT. Evidence has accumulated for a role of toxic oxygen radicals in the pathogenesis of ischemia-reperfusion injury in the kidney. The aim of this study was to evaluate the hypothesis that reducing postischemic renal injury is possible by delivery of the gene for the antioxidant enzyme superoxide dismutase (SOD). Female Sprague-Dawley rats received intravenous injections of recombinant adenovirus (1 x 10⁹ pfu) containing the transgenes for Escherichia coli ß-galactosidase (Ad-LacZ, as control) or human Cu/Zn-SOD (Ad-SOD). Three days later, renal ischemia was produced by cross-clamping the left renal vessels for 60 min. The right kidney was removed before reperfusion and processed for the transgene. Renal SOD protein and activity in rats given Ad-SOD was 2.5-fold higher than from the animals receiving Ad-LacZ. Urinary lactate dehydrogenase concentrations were elevated by ischemia-reperfusion in the Ad-LacZ group (1403 ± 112 U/L), yet values were 50% lower in Ad-SOD-treated rats. Free radical production was elevated by ischemia-reperfusion but was significantly lower in SOD-treated animals. Importantly, on postischemic day 1, glomerular filtration rates were reduced to 0.21 ml/min per 100 g in the Ad-LacZ group, whereas values remained significantly higher (0.39) in the Ad-SOD group. Two weeks after ischemia-reperfusion, inflammation, interstitial fibrosis, tubular atrophy and tissue levels of tumor necrosis factor alpha and interleukin-1 were significantly higher in the Ad-LacZ-treated than in Ad-SOD-treated rats. In conclusion, these results indicate that SOD expression can be increased by delivery of the sod gene to the kidney by intravenous injection and that sod gene transduction minimized ischemia-reperfusion-induced acute renal failure.

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