Role of iron in postischemic renal injury in the rat

Abstract

To determine whether iron participates in free radical-mediated postischemic renal injury and lipid peroxidation, we examined the effects of removal of endogenous iron or provision of exogenous iron following renal ischemia, as well as the effects of renal ischemia and reperfusion on renal venous and urinary 'free' iron. Rats underwent 60 minutes of renal ischemia and were studied after either 24 hours (inulin clearance) or 15 minutes (renal malondialdehyde content) of reperfusion. Infusion of the iron chelator deferoxamine (200 mg/kg/hr) during the first 60 minutes of reperfusion resulted in a marked improvement in renal function (inulin clearance: 879 ± 154 vs. 74 μl/min; P < 0.025) and a reduction in lipid peroxidation (renal malondialdehyde: 0.449 ± 0.06 vs. 0.698 ± 0.08 mmol/mg prot; P < 0.05) compared to control animals. Infusion of 50 mg/kg/hr deferoxamine also protected renal function after ischemia (inulin clearance: 624 ± 116 vs. 285 ± 90 μl/min; P < 0.05) and resulted in less histologic injury. Iron-saturated deferoxamine had no protective effect. Conversely, infusion of the iron complex EDTA-FeCl3 during reperfusion exacerbated postischemic renal dysfunction and lipid peroxidation. Following renal ischemia there was no detectable increase in 'free' iron in arterial or renal venous plasma. However, urinary 'free' iron increased 10- to 20-fold following reperfusion. Iron chelators which underwent filtration and gained access to this free iron in the urine (free deferoxamine or inulin-conjugated deferoxamine) provided protection, whereas a chelator confined to the vascular space (dextran-conjugated deferoxamine) did not. We propose that during ischemia and reperfusion iron released from storage pools and is available to catalyze hydroxyl radical formation and lipid peroxidation. Administration of the iron chelator deferoxamine during reperfusion limits postischemic renal dysfunction and free radical-mediated lipid peroxidation. These effects appear to take place in the urinary space or along the brush border membrane adjacent to the urinary space.