title: Amelioration of cisplatin nephrotoxicity by genetic or pharmacologic blockade of prostaglandin synthesis.
abstract: 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-α and renal levels of IL-1β, 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.
authors.affiliation: Department of Internal Medicine, University of Utah, Salt Lake City, Utah 84132, USA.
authors.forename: Zhanjun
authors.initials: Z
authors.lastname: Jia
authors.forename: Ningning
authors.initials: N
authors.lastname: Wang
authors.forename: Toshinori
authors.initials: T
authors.lastname: Aoyagi
authors.forename: Haiping
authors.initials: H
authors.lastname: Wang
authors.forename: Haiying
authors.initials: H
authors.lastname: Liu
authors.forename: Tianxin
authors.initials: T
authors.lastname: Yang
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001806:Blood Urea Nitrogen; D000068579:Celecoxib; D002945:Cisplatin / Q000009:adverse effects* / Q000494:pharmacology; D003404:Creatinine / Q000097:blood; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis*; D015870:Gene Expression / Q000187:drug effects* / Q000235:genetics*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D000071876:Prostaglandin-E Synthases; D011720:Pyrazoles / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D053583:Interleukin-1beta; D011720:Pyrazoles; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; D016718:Arachidonic Acid; D003404:Creatinine; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D000068579:Celecoxib; D015232:Dinoprostone; D002945:Cisplatin