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

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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.

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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

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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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Authors and Affiliations

  1. Division of Biomedical Science, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, 305-8575, Japan

    Kosuke Okada, Dongmei Ma, Eiji Warabi, Kentaro Akiyama, Yasuhiro Murata & Tetsuro Ishii

  2. Division of Medical Science, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, 305-8575, Japan

    Kosuke Okada & Junichi Shoda

  3. Pathophysiology of Renal Diseases, Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, 305-8575, Japan

    Naoki Morito

  4. Oral and Maxillofacial Surgery, Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, 305-8575, Japan

    Kenji Yamagata, Hiroki Bukawa & Toru Yanagawa

Authors
  1. Kosuke Okada
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  2. Dongmei Ma
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  3. Eiji Warabi
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  10. Tetsuro Ishii
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  11. Toru Yanagawa
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Correspondence to Toru Yanagawa.

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Okada, K., Ma, D., Warabi, E. et al. Amelioration of cisplatin-induced nephrotoxicity in peroxiredoxin I-deficient mice. Cancer Chemother Pharmacol 71, 503–509 (2013). https://doi.org/10.1007/s00280-012-2046-0

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  • DOI: https://doi.org/10.1007/s00280-012-2046-0

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