title: Amelioration of cisplatin-induced nephrotoxicity in peroxiredoxin I-deficient mice.
abstract: OBJECTIVE
  Cisplatin is one of the most potent chemotherapeutic agents used to treat cancer. However, cisplatin-induced nephrotoxicity, which is partly caused by oxidative damage, is a serious problem. We previously showed that murine embryonic fibroblasts deficient in Peroxiredoxin I (Prx I), a major Nrf2-linked anti-oxidant enzyme, are susceptible to cisplatin-induced cytotoxicity. In the present study, we examined the role of Prx I against cisplatin-induced renal injury in vivo using Prx                   I-null mice.
  
  
  METHODS
  Prx I-null mice and wild-type (WT) mice were given an intraperitoneal injection of cisplatin, and tissues were removed and evaluated histopathologically. In addition, gene and protein expression of efflux transporters was analyzed.
  
  
  RESULTS
  In contrast to an in vitro cell study, Prx I-null mice exhibited less cisplatin-induced renal damage than WT mice in histological and blood biochemical analyses. Moreover, Prx I-null mice showed a higher clearance rate of cisplatin than WT mice following intraperitoneal cisplatin injection. Consistent with these results, Prx I-null mice exhibited higher expression of renal efflux transporters Mrp2 and Mrp4 compared with WT mice under both basal and the cisplatin-induced conditions. We suggest the enhanced transcriptional activity of c-Myc in Prx I-null mice may partly contribute the enhanced expression of renal efflux transporters.
  
  
  CONCLUSIONS
  In summary, the enhanced clearance rate of cisplatin significantly attenuates nephrotoxicity in Prx I-null mice.
authors.affiliation: Division of Biomedical Science, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Okada
authors.forename: Dongmei
authors.initials: D
authors.lastname: Ma
authors.forename: Eiji
authors.initials: E
authors.lastname: Warabi
authors.forename: Naoki
authors.initials: N
authors.lastname: Morito
authors.forename: Kentaro
authors.initials: K
authors.lastname: Akiyama
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Murata
authors.forename: Kenji
authors.initials: K
authors.lastname: Yamagata
authors.forename: Hiroki
authors.initials: H
authors.lastname: Bukawa
authors.forename: Junichi
authors.initials: J
authors.lastname: Shoda
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Ishii
authors.forename: Toru
authors.initials: T
authors.lastname: Yanagawa
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002945:Cisplatin / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000502:physiology; D054464:Peroxiredoxins / Q000172:deficiency* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D002945:Cisplatin; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D054464:Peroxiredoxins; C489540:Abcc4 protein, mouse; C489899:Prdx1 protein, mouse