EXPERIMENTAL ISCHEMIA AND REPERFUSION INJURY

Q. Peng, G. Xing, K. Li, N. Wang, S.H. Sacks, W. Zhou
Mrc Centre For Transplantation, King's College London, London/UNITED KINGDOM

Body: Introduction: Renal ischemia/reperfusion (I/R) injury is a major cause of morbidity in both native and allograft kidneys. Anaphylatoxins C5a and C3a generated by complement activation have broad pro-inflammatory potential. However, their roles in renal I/R injury are not well-defined. In this study, we evaluated the contribution of C3aR or/and C5aR activation to renal I/R injury. Methods: We employed a renal I/R injury model and used wild type and several knockout mouse strains [single deficiency (C5aR-/- or C3aR-/-), double deficiency (C5aR-/-/C3aR-/-)]. Renal I/R injury was induced by bilaterally clamping renal arteries and veins for 30 min following by releasing clips to let kidney to be reperfused. Kidneys and blood samples were taken at different time points (6, 24, 48h) after ischemic insult. Renal functional impairment [blood urea nitrogen (BUN), renal tissue damage and cellular infiltration were assessed. Gene expressions of pro-inflammatory cytokines, chemokines, adhesion molecules and tubule injury marker (HAVCR-1) in injured tissue were analysed. Results: We found that both the double deficient mice (C5aR-/-/C3aR-/-) and the single deficient mice (C5aR-/- or C3aR-/-) had significantly lower levels of BUN, less renal tissue damage and fewer infiltrating cells within renal tissue compared to the wild type mice, and the extent of BUN and tissue damage in the double deficient mice was also significantly less than those in both the single deficient mice. Furthermore, gene expressions of HAVCR-1, pro-inflammatory cytokines (IL-1β, IFN-γ), chemokines (KC, MIP-1α, MIP-1β, MCP-1), adhesion molecules (ICAM-1, PECAM-1), and endothelial activation/injury markers (CD146, vWf) in injured kidney were significantly lower in the double deficient mice meanwhile the degrees of reductions of those expressions in both the single deficient mice may be varied compared with the wild type mice. Conclusion: These findings provide profound evidence to suggest that both C3a and C5a play a synergistic role in pathogenesis of renal I/R injury through C3a/C5a mediated leukocyte accumulation, up-regulation of pro-inflammatory cytokine and chemokine production, and activation of endothelial cells. Finally, our data suggests that effective therapeutic approach to prevent renal I/R injury may require targeting both C3aR and C5aR signalling pathways.

Disclosure: All authors have declared no conflicts of interest.