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This Article Full Text Full Text (PDF) All Versions of this Article: 296/3/F496    most recent 90443.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Pan, H. Articles by Gao, B. Search for Related Content PubMed PubMed Citation Articles by Pan, H. Articles by Gao, B.

Anaphylatoxin C5a contributes to the pathogenesis of cisplatin-induced nephrotoxicity

¹Department of Urology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Zhejiang, China; Sections on ²Liver Biology and ³Oxidative Stress Tissue Injury, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland; and ⁴Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts

Submitted 29 July 2008 ; accepted in final form 7 January 2009

Nephrotoxicity is a common complication of cisplatin chemotherapy that limits its clinical use; however, the mechanisms underlying cisplatin-mediated nephrotoxicity are not fully understood. In this study, we investigated the role of anaphylatoxin C5a in the pathogenesis of cisplatin-mediated nephrotoxicity. Our data show that cisplatin-induced renal injury is significantly reduced in C5- or C5aR-deficient mice. However, pretreatment with C5 or C5a restores sensitivity to cisplatin-induced nephrotoxicity in C5-deficient mice. In wild-type mice, administration of cisplatin triggers the increased renal expression of multiple cytokines and caspases. This induction is diminished in C5-deficient mice, which is restored by pretreatment with C5 or C5a proteins. Interestingly, renal injury induced by cisplatin is similar between wild-type and CD59ab double knockout mice, and the formation of membrane attack complexes (MACs) by cisplatin in the kidney is diminished in C5-deficient mice, but not in C5aR-deficient mice. In conclusion, our findings suggest that C5a plays an important role in the pathogenesis of cisplatin nephrotoxicity. Likely, C5a binds to C5aR, leading to induction of proinflammatory cytokines and inflammation. The formation of MACs does not appear to contribute to the nephrotoxicity of cisplatin based on our study results.

cytokines; caspase; STAT3; NF-B