title: Independent pathways of P-selectin and complement-mediated renal ischemia/reperfusion injury.
abstract: Evidence from in vitro studies indicates that complement activation regulates the expression of P-selectin on endothelial cells. This suggests that in disorders such as ischemia/reperfusion injury, in which both complement and P-selectin have been shown to play a role, complement activation is a primary event and the effects of P-selectin are secondary. To test this hypothesis in vivo, we examined a mouse kidney model of ischemia/reperfusion injury. Surprisingly, the time course and extent of expression of P-selectin was unaltered in C3-deficient mice compared with wild-type mice, in which there was rapid but transient up-regulation of P-selectin on capillary walls and slower accumulation of complement split product on the tubular epithelium. In addition, treatment with anti-P-selectin antibody to reduce the neutrophil-mediated reperfusion damage was equally effective in the absence of C3. These data imply that complement and P-selectin-mediated pathways of renal reperfusion injury are mutually independent, a conclusion that is possibly explained by the differences in the location and time kinetics of complement activation and P-selectin expression. We conclude that in vivo interaction between complement and P-selectin is limited because of time and spatial considerations. Consequently, complement and P-selectin pose distinct targets for therapy.
authors.affiliation: Department of Nephrology and Transplantation, Guy's Hospital, London, United Kingdom.
authors.forename: Conrad A
authors.initials: CA
authors.lastname: Farrar
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.forename: Steven H
authors.initials: SH
authors.lastname: Sacks
authors.forename: Wuding
authors.initials: W
authors.lastname: Zhou
mesh_terms: D000818:Animals; D003167:Complement Activation / Q000502:physiology*; D003176:Complement C3 / Q000172:deficiency / Q000378:metabolism; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism; D007150:Immunohistochemistry; D007668:Kidney / Q000098:blood supply / Q000473:pathology*; D008297:Male; D051379:Mice; D009504:Neutrophils / Q000502:physiology; D019007:P-Selectin / Q000378:metabolism*; D015427:Reperfusion Injury / Q000473:pathology*; D015398:Signal Transduction / Q000502:physiology*; D013997:Time Factors
chemical_list: D003176:Complement C3; D019007:P-Selectin