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(American Journal of Pathology. 2004;164:133-141.)
© 2004 American Society for Investigative Pathology

Independent Pathways of P-Selectin and Complement-Mediated Renal Ischemia/Reperfusion Injury

Conrad A. Farrar*, Yi Wang{dagger}, Steven H. Sacks* and Wuding Zhou*

From the Department of Nephrology and Transplantation,* Guy’s Hospital, London, United Kingdom; and Alexion Pharmaceuticals,{dagger} New Haven, Connecticut

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.




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