Role of xanthine oxidase in ischemia/reperfusion injury

Abstract

Oxygen metabolites formed during reperfusion of ischemic kidneys prevent recovery of renal function after short periods of renal ischemia. Xanthine oxidase has been proposed as a source of toxic oxygen metabolites during reperfusion of ischemic kidneys. To determine whether the enzyme is converted from the non-oxygen metabolite-producing dehydrogenase (type D) to the oxygen metabolite-producing oxidase (type O), we measured type D and O (total, reversible, and irreversible) xanthine oxidase in renal cortical homogenates after 30 min of ischemia in vivo and 60 min of reperfusion by the isolated perfused kidney technique. Total enzyme activity (type D plus type O) was not altered by ischemia or reperfusion. Compared with nonischemic conditions, ischemia increased total type O (53 .+-. 5 vs. 21 .+-. 3%, P < 0.01) and reversible type O (15.4 .+-. 1.5 vs. 2.1 .+-. 1.4 U/g) xanthine oxidase activities. Reperfusion further increased total type O (82 .+-. 3%) and reversible type O (27.7 .+-. 3.3 U/g, both P < 0.01 vs. nonischemic perfusions) xanthine oxidase activities. To determine the physiological role of xanthine oxidase in renal ischemia, we depleted rats of xanthine oxidase by feeding tungsten. After 4 wk of tungsten, renal xanthine oxidase levels were reduced by > 90% and renal function was markedly improved during reperfusion. For example, after 30 min of ischemia and 60 min of reperfusion, glomerular filtration rate was 457 .+-. 25 .mu.l. min-1 g-1 and tubular sodium reabsorption was 92 .+-. 2% in tungsten-treated rats compared with 144 .+-. 15 .mu.l .cntdot. min-1 g-1 and 71 .+-. 4% (both P < 0.01) in non-tungsten-treated rats. We conclude that xanthine oxidase is converted from type D to type O (predominantly reversible) during both ischemia and reperfusion and that xanthine oxidase is an important source of deleterious oxygen metabolites during reperfusion of ischemic kidneys.