Published online before print September 4, 2008

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(American Journal of Pathology. 2008;173:973-980.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.080103

Gene Silencing of Complement C5a Receptor Using siRNA for Preventing Ischemia/Reperfusion Injury

Xiufen Zheng^*, Xusheng Zhang^*, Biao Feng^*, Hongtao Sun^*, Motohiko Suzuki^*, Thomas Ichim^*, Norihiko Kubo^*, Arthur Wong^*, Lisa R. Min^*, Marianne E. Budohn^*, Bertha Garcia^*, Anthony M. Jevnikar^* and Wei-Ping Min^*

From the Departments of Surgery,^* Pathology, Medicine, Microbiology and Immunology, University of Western Ontario; Multi-Organ Transplant Program, London Health Sciences Centre; and Transplantation and Regenerative Medicine, Lawson Health Research Institute; London, Ontario, Canada

Ischemia/reperfusion (I/R) injury in organ transplantation significantly contributes to graft failure and is untreatable using current approaches. I/R injury is associated with activation of the complement system, leading to the release of anaphylatoxins, such as C5a, and the formation of the membrane attack complex. Here, we report a novel therapy for kidney I/R injury through silencing of the C5a receptor (C5aR) gene using siRNA. Mice were injected with 50 µg of C5aR siRNA 2 days before induction of ischemia. Renal ischemia was then induced through clamping of the renal vein and artery of the left kidney for 25 minutes. The therapeutic effects of siRNA on I/R were evaluated by assessment of renal function, histopathology, and inflammatory cytokines. siRNA targeting C5aR efficiently inhibited C5aR gene expression both in vitro and in vivo. Administering C5aR siRNA to mice preserved renal function from I/R injury, as evidenced by reduced levels of serum creatinine and blood urea nitrogen in the treated groups. Inhibition of C5aR also diminished in vivo production of the pro-inflammatory cytokine tumor necrosis factor- and chemokines MIP-2 and KC, resulting in the reduction of neutrophils influx and cell necrosis in renal tissues. This study demonstrates that siRNA administration represents a novel approach to preventing renal I/R injury and may be used in a variety of clinical settings, including transplantation and acute tubular necrosis.