title: Urinary chemokine (C-C motif) ligand 2 (monocyte chemotactic protein-1) as a tubular injury marker for early detection of cisplatin-induced nephrotoxicity.
abstract: Because of the difficulty in detecting segment-specific response in the kidney, we investigated the molecular events underlying acute kidney injury in the proximal tubules of rats with cisplatin (cis-diamminedichloroplatinum II)-induced nephrotoxicity. Microarray analysis revealed that mRNA levels of several cytokines and chemokines, such as interleukin-1beta, chemokine (C-C motif) ligand (CCL) 2, CCL20, chemokine (C-X-C motif) ligand (CXCL) 1, and CXCL10 were significantly increased after cisplatin treatment in both isolated proximal tubules and whole kidney. Interestingly, tubular CCL2 mRNA levels increased soon after cisplatin administration, whereas CCL2 mRNA levels in whole kidney first decreased and then increased. Levels of both CCL2 and kidney injury molecule-1 (KIM-1) in the whole kidney increased after cisplatin administration. Immunofluorescence analysis revealed CCL2 changes in the proximal tubular cells initially and then in the medullary interstitium. Urinary CCL2 excretion significantly increased approximately 3-fold compared with controls the day after cisplatin administration (5mg/kg), when no changes were observed plasma creatinine and blood urea nitrogen levels. Urinary levels of KIM-1 also increased 3-fold after cisplatin administration. In addition, urinary CCL2 rather than KIM-1 increased in chronic renal failure rats after administration of low-dose cisplatin (2mg/kg), suggesting that urinary CCL2 was selective for cisplatin-induced nephrotoxicity in renal impairment. These results indicated that the increase in cytokine and chemokine expression in renal epithelial cells might be responsible for kidney deterioration in cisplatin-induced nephrotoxicity, and that urinary CCL2 is associated with tubular injury and serves as a sensitive and noninvasive marker for the early detection of cisplatin-induced tubular injury.
authors.affiliation: Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Nishihara
authors.forename: Satohiro
authors.initials: S
authors.lastname: Masuda
authors.forename: Haruka
authors.initials: H
authors.lastname: Shinke
authors.forename: Aiko
authors.initials: A
authors.lastname: Ozawa
authors.forename: Takaharu
authors.initials: T
authors.lastname: Ichimura
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yonezawa
authors.forename: Shunsaku
authors.initials: S
authors.lastname: Nakagawa
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Inui
authors.forename: Joseph V
authors.initials: JV
authors.lastname: Bonventre
authors.forename: Kazuo
authors.initials: K
authors.lastname: Matsubara
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D015415:Biomarkers; D015815:Cell Adhesion Molecules / Q000378:metabolism / Q000652:urine; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism / Q000652:urine*; D002945:Cisplatin / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000187:drug effects; D007674:Kidney Diseases / Q000139:chemically induced*; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D040081:Protein Array Analysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D059467:Transcriptome
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D015815:Cell Adhesion Molecules; D018932:Chemokine CCL2; D002945:Cisplatin; D012333:RNA, Messenger; C491766:Ccl2 protein, rat; C110936:Havcr1 protein, rat