Inhibiting the complement system does not reduce injury in renal ischemia reperfusion.
The complex pathogenesis of ischemia reperfusion injury (IRI) includes endothelial expression of adhesion molecules, leukocyte recruitment and activation, reactive oxygen species production, and apoptotic and necrotic cell death. A role for complement in IRI of different organs, including kidney, has been proposed on the basis of results of experiments that used pharmacologic inhibitors as well as animals that were deficient in individual complement proteins. Here, renal IRI in mice was examined. Animals that were deficient 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 -/- mice, it was investigated, by use of the rodent C3 convertase inhibitor CR1-related gene/protein y-Ig (Crry-Ig), whether exogenous administration of a complement inhibitor could lessen renal injury. Despite the use of Crry-Ig in 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 examination 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-treated animals, C3 deposition was inversely proportional to BUN values (r = -0.63; P < 0.001), which presumably indicates that severe vascular IRI allowed access of the 160 kD Crry-Ig to the interstitium. Thus, renal IRI in mice may have a partial complement dependence, yet pharmacologic inhibition of the complement system does not seem to be effective, likely because of the presence of other mediator systems that operate in parallel.
Park
Pierce
P
Department of Medicine, Section of Nephrology, The University of Chicago, Chicago, Illinois.
Haas
Mark
M
Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
Cunningham
Patrick N
PN
Department of Medicine, Section of Nephrology, The University of Chicago, Chicago, Illinois.
Alexander
Jessy J
JJ
Department of Medicine, Section of Nephrology, The University of Chicago, Chicago, Illinois.
Bao
Lihua
L
Department of Medicine, Section of Nephrology, The University of Chicago, Chicago, Illinois.
Guthridge
Joel M
JM
Department of Medicine, Division of Rheumatology, University of Colorado Health Sciences Center, Denver, Colorado.
Kraus
Damian M
DM
Department of Medicine, Division of Rheumatology, University of Colorado Health Sciences Center, Denver, Colorado.
Holers
V Michael
VM
Department of Medicine, Division of Rheumatology, University of Colorado Health Sciences Center, Denver, Colorado.
Quigg
Richard J
RJ
Department of Medicine, Section of Nephrology, The University of Chicago, Chicago, Illinois.
D000818:Animals; D003176:Complement C3 / Q000172:deficiency / Q000378:metabolism; D003169:Complement Inactivator Proteins / Q000494:pharmacology*; D007511:Ischemia / Q000473:pathology* / Q000503:physiopathology; D007668:Kidney / Q000187:drug effects* / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017463:Receptors, Complement 3b / Q000172:deficiency; D017464:Receptors, Complement 3d / Q000172:deficiency; D012079:Renal Circulation; D015427:Reperfusion Injury / Q000473:pathology* / Q000503:physiopathology; D013194:Staining and Labeling
D003176:Complement C3; D003169:Complement Inactivator Proteins; D017463:Receptors, Complement 3b; D017464:Receptors, Complement 3d