O2 metabolites cause reperfusion injury after short but not prolonged renal ischemia.
Toxic O2 metabolites have been postulated to contribute to renal ischemia-reperfusion injury, but their biochemical assessment and contribution as a function of the duration of ischemia is unclear. To address this issue we measured renal function and renal cortical glutathione levels following 20, 30, or 45 min of ischemia in situ and then 60 min of reperfusion by the isolated kidney technique. Increasing durations of ischemia were associated with progressive decreases in perfusion flow rate, glomerular filtration rate, tubular Na reabsorption, and renal cortical glutathione following reperfusion. However, reperfusion following simultaneous addition of the permeable O2 metabolite scavenger dimethylthiourea (DMTU; but not urea) prevented glutathione consumption and attenuated reperfusion-induced injury after 20 and 30 min of ischemia. In contrast, reperfusion with DMTU prevented glutathione consumption but did not improve renal function after 45 min of ischemia. Similarly, reperfusion with dimethyl sulfoxide also attenuated renal injury after 20 and 30 min, but not after 45 min of ischemia. Thus reperfusion of kidneys made ischemic for 20 or 30 min is associated with decreases in tissue glutathione and renal function that were both inhibitable by addition of O2 metabolite scavengers during reperfusion. In contrast, addition of O2 metabolite scavengers during reperfusion of kidneys previously made ischemic for 45 min prevented decreases in glutathione but did not improve renal function. We conclude that O2 metabolites formed during reperfusion contribute to functional impairment in kidneys made ischemic for short durations up to 30 min) but that after prolonged ischemia (greater than 30 min) injury is primarily mediated by non-O2 metabolite-dependent cellular events.
D000818:Animals; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D005919:Glomerular Filtration Rate; D005978:Glutathione / Q000378:metabolism; D007511:Ischemia; D007674:Kidney Diseases / Q000378:metabolism*; D008297:Male; D010100:Oxygen / Q000378:metabolism*; D010477:Perfusion; D051381:Rats; D011919:Rats, Inbred Strains; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology
C038983:1,3-dimethylthiourea; D005978:Glutathione; D013890:Thiourea; D010100:Oxygen; D004121:Dimethyl Sulfoxide