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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

Abstract

Purpose

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.

Conclusion

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

Keywords

Peroxiredoxin I Cisplatin Nephrotoxicity Mrp c-Myc 

Abbreviations

ARF

Acute renal failure

BUN

Blood urea nitrogen

GSH

Glutathione

MDR

Multidrug resistance

Mrp

Multidrug resistance-associated protein

Nrf2

Nuclear factor-E2-related factor-2

pAb

Polyclonal antibody

Prx

Peroxiredoxin

ROS

Reactive oxygen species

TRX

Thioredoxin

Notes

Acknowledgments

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

None.

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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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