Journal
KIDNEY INTERNATIONAL
Volume 79, Issue 1, Pages 77-88Publisher
ELSEVIER SCIENCE INC
DOI: 10.1038/ki.2010.331
Keywords
cisplatin; cyclooxygenase-2; cytokines; microsomal prostaglandin E synthase-1; nephrotoxicity
Categories
Funding
- NIH [DK079162]
- American Heart Association
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK079162] Funding Source: NIH RePORTER
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Nephrotoxicity is a common complication of cisplatin chemotherapy that limits its clinical use. Here, we determined whether arachidonic acid metabolism has a role in the pathogenesis of cisplatin nephrotoxicity in mice. Three days following cisplatin injection, wild-type mice displayed renal functional and structural abnormalities consistent with nephrotoxicity accompanied by elevated circulating and renal levels of TNF-alpha and renal levels of IL-1 beta, subunits of NADPH oxidase, thiobarbituric acid-reactive substances, and PGE(2). These indices of kidney injury, inflammation, oxidative stress, and arachidonate metabolism were all diminished in microsomal prostaglandin E synthase-1 (mPGES-1) null mice; a phenotype recapitulated by treatment of wild-type mice with the COX-2 inhibitor celecoxib. Following cisplatin administration, there was paralleled induction of COX-2 and mPGES-1 in renal parenchymal cells. Interestingly, mPGES-1 null mice were not protected from acute kidney injury caused by ischemia-reperfusion or endotoxin. Hence, our results suggest the activation of COX-2/mPGES-1 pathway in renal parenchymal cells may selectively mediate cisplatin-induced renal injury. This may offer a novel therapeutic target for management of the adverse effect of cisplatin chemotherapy. Kidney International (2011) 79, 77-88; doi: 10.1038/ki.2010.331; published online 15 September 2010
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