Renal work, glutathione and susceptibility to free radical-mediated postischemic injury

Renal work, glutathione and susceptibility to free radical-mediated postischemic injury. Studies were performed to determine whether renal glutathione (GSH) is an important free-radical scavenger following ischemia and reperfusion, whether alterations in renal transport work affect renal GSH levels, and whether a decrease in renal work decreases susceptibility to postischemic renal injury via the first two effects. Following administration of either intravenous GSH to increase renal GSH or intraperitoneal diethylmaleate to decrease renal GSH, Sprague-Dawley rats underwent 60 minutes of renal ischemia. In animals with high renal GSH following GSH infusion, GFR 24 hours after ischemia was 0.43 ± 0.08ml/min compared to 0.15 ± 0.02ml/min in saline-infused control animals (P < 0.01). When renal GSH was decreased by the administration of diethylmaleate postischemic renal dysfunction was accentuated. Twenty-four hours after ischemia GFR was 0.05 ± 0.02ml/min in diethylmaleate-treated animals and 0.28 ± 0.06ml/min in control animals (P < 0.005). To test whether a decrease in renal transport work alters renal GSH the filtered load of sodium was reduced by producing unilateral renal artery stenosis. Alternatively, renal work was lessened when sodium reabsorption was interfered with by the infusion of a combination of natriuretic agents. Renal artery stenosis produced a 37% decrease in GFR. Renal GSH was 0.435 ± 0.089 nmol/mg protein in intact kidneys and 0.804 ± 0.239 nmol/mg protein in stenotic kidneys {P < 0.05). The infusion of natriuretic agents produced no change in GFR or renal plasma flow but resulted in a striking elevation in renal GSH. Kidneys from rats infused with saline for two hours had a renal GSH level of 0.833 ± 0.084 nmol/mg protein, whereas kidneys from rats infused with the natriuretic agents for two hours had a GSH level of 1.669 ± 0.418 nmol/mg protein (P < 0.01). To determine whether a decrease in renal work alters susceptibility to ischemic renal injury, rats with 24 hours of unilateral renal artery stenosis were subjected to 60 minutes of bilateral renal artery occlusion. Although kidneys that had been stenotic had a lower GFR in the basal state, 24 hours after ischemia GFR was higher in previously stenotic kidneys (0.31 ± 0.06ml/min vs. 0.18 ± 0.05ml/min in previously intact kidneys, P < 0.025). Therefore, GFR fell by 84% in previously intact kidneys but only 55% in previously stenotic kidneys. Kidneys which had previously been stenotic also underwent less lipid peroxidation sifter ischemia and reperfusion as evidenced by significantly lower renal malondialdehyde content after ischemia plus 15 minutes of reperfusion. In addition, renal histologic examination revealed significantly less injury in previously stenotic kidneys compared with previously intact kidneys from the same animal. These studies are consistent with previous findings of protection against free radical-mediated injury in hypothyroid animals and suggest that a decrease in the base line level of renal transport work results in higher renal GSH levels. Since renal GSH is an important free radical scavenger during postischemic reperfusion, alterations in renal transport work affect susceptibility to free radical-mediated postischemic injury through changes in renal GSH