Inhibiting the complement system does not reduce injury in renal ischemia reperfusion

The complex pathogenesis of ischemia reperfusion injury (IRI) includes endo thelial expression of adhesion molecules, leukocyte recruitment and activat ion, reactive oxygen species production, and apoptotic and necrotic cell de ath. A role for complement in IRI of different organs, including kidney, ha s been proposed on the basis of results of experiments that used pharmacolo gic inhibitors as well as animals that were deficient in individual complem ent proteins. Here, renal IRI in mice was examined. Animals that were defic ient in C3 had partial protection from IRI induced by 27.5 min of bilateral renal ischemia, followed by 20 h of reperfusion (blood urea nitrogen [BUN] values, 46.6 +/- 6.9 and 68.4 +/- 7.9 mg/dl in C3 -/- and C3 +/+ mice; n = 7 and 8, respectively; P = 0.033). Given the reduction in IRI in C3 -/- mi ce, it was investigated, by use of the rodent C3 convertase inhibitor CRI-r elated gene/protein y-Ig (Crry-Ig), whether exogenous administration of a c omplement inhibitor could lessen renal injury. Despite the use of Crry-Ig i n high doses, there was no significant reduction of injury induced by 20 to 30 min of ischemia followed by up to 30 h of reperfusion. Histologic exami nation revealed acute tubular necrosis and neutrophilic infiltration, both of which correlated significantly with BUN values (P = 0.001). Of interest, C3 deposition around renal tubules was significantly less in animals with IRI, compared with that in unmanipulated controls (P < 0.001). In Crry-Ig-t reated animals, C3 deposition was inversely proportional to BUN values (r = -0.63; P < 0.001), which presumably indicates that severe vascular IRI all owed access of the 160 kD Crry-Ig to the interstitium. Thus, renal IRI in m ice may have a partial complement dependence, yet pharmacologic inhibition of the complement system does not seem to be effective, likely because of t he presence of other mediator systems that operate in parallel.