title: Predominant role for C5b-9 in renal ischemia/reperfusion injury.
abstract: Previous work has indicated that complement is a mediator of ischemia/reperfusion (I/R) injury. To investigate the components of complement responsible for this effect, we examined a model of renal I/R injury in C3-, C4-, C5-, and C6-deficient mice. We occluded the renal arteries and veins (40-58 minutes) and, after reperfusion (0-72 hours), assessed renal structural and functional injury. C3-, C5-, and C6-deficient mice were protected from renal I/R injury, whereas C4-deficient mice were not protected. C6-deficient mice treated with antibody to block C5a generation showed no additional protection from I/R injury. Reconstitution with C6 alone restored the I/R injury in C6-deficient mice. Tubular epithelial cells were the main structures damaged by complement-mediated attack, and, in contrast, the renal vessels were spared. Neutrophil infiltration and myeloperoxidase activity were reduced in C-deficient mouse kidney, but by a similar extent in C3-deficient and C6-deficient mice. We conclude that the membrane attack complex of complement (in which C5 and C6 participate) may account for the effect of complement on mouse renal I/R injury. Neither C5a-mediated neutrophil infiltration nor the classic pathway, in which C4 participates, appears to contribute to I/R injury in this model. By contrast with other organs, such as the heart, the primary effect of complement in the ischemic area is on the parenchymal cell rather than the vascular endothelial cell. The membrane attack complex of complement is a potential target for prevention of I/R injury in this model.
authors.affiliation: Department of Nephrology and Transplantation, Guy's Hospital, London, United Kingdom.
authors.forename: W
authors.initials: W
authors.lastname: Zhou
authors.forename: C A
authors.initials: CA
authors.lastname: Farrar
authors.forename: K
authors.initials: K
authors.lastname: Abe
authors.forename: J R
authors.initials: JR
authors.lastname: Pratt
authors.forename: J E
authors.initials: JE
authors.lastname: Marsh
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: G L
authors.initials: GL
authors.lastname: Stahl
authors.forename: S H
authors.initials: SH
authors.lastname: Sacks
mesh_terms: D000818:Animals; D003167:Complement Activation; D003176:Complement C3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D003181:Complement C4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D003182:Complement C5 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D003183:Complement C6 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015938:Complement Membrane Attack Complex / Q000378:metabolism*; D004195:Disease Models, Animal; D007668:Kidney / Q000098:blood supply* / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000201:enzymology / Q000473:pathology; D009195:Peroxidase / Q000378:metabolism; D015427:Reperfusion Injury / Q000209:etiology / Q000276:immunology* / Q000473:pathology
chemical_list: D003176:Complement C3; D003181:Complement C4; D003182:Complement C5; D003183:Complement C6; D015938:Complement Membrane Attack Complex; D009195:Peroxidase