Cancer Chemotherapy and Pharmacology

, Volume 71, Issue 2, pp 503–509 | Cite as

Amelioration of cisplatin-induced nephrotoxicity in peroxiredoxin I-deficient mice

  • Kosuke Okada
  • Dongmei Ma
  • Eiji Warabi
  • Naoki Morito
  • Kentaro Akiyama
  • Yasuhiro Murata
  • Kenji Yamagata
  • Hiroki Bukawa
  • Junichi Shoda
  • Tetsuro Ishii
  • Toru Yanagawa
Original Article



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.


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.


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.


In summary, the enhanced clearance rate of cisplatin significantly attenuates nephrotoxicity in Prx I-null mice.


Peroxiredoxin I Cisplatin Nephrotoxicity Mrp c-Myc 



Acute renal failure


Blood urea nitrogen




Multidrug resistance


Multidrug resistance-associated protein


Nuclear factor-E2-related factor-2


Polyclonal antibody




Reactive oxygen species





The first two authors (K.O. and D.M.) contributed equally to this work. This research was supported by the Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (B), and Grant-in-Aid for Challenging Exploratory Research (T.Y.). We would like to thank Prof. G.E, Mann whose comments and suggestions were of inestimable value for this study.

Conflict of interest



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Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Kosuke Okada
    • 1
    • 2
  • Dongmei Ma
    • 1
  • Eiji Warabi
    • 1
  • Naoki Morito
    • 3
  • Kentaro Akiyama
    • 1
  • Yasuhiro Murata
    • 1
  • Kenji Yamagata
    • 4
  • Hiroki Bukawa
    • 4
  • Junichi Shoda
    • 2
  • Tetsuro Ishii
    • 1
  • Toru Yanagawa
    • 4
  1. 1.Division of Biomedical Science, Faculty of MedicineUniversity of TsukubaTsukubaJapan
  2. 2.Division of Medical Science, Faculty of MedicineUniversity of TsukubaTsukubaJapan
  3. 3.Pathophysiology of Renal Diseases, Division of Clinical Medicine, Faculty of MedicineUniversity of TsukubaTsukubaJapan
  4. 4.Oral and Maxillofacial Surgery, Division of Clinical Medicine, Faculty of MedicineUniversity of TsukubaTsukubaJapan

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