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Research ArticleArticle

Renal Circadian Clock Regulates the Dosing-Time Dependency of Cisplatin-Induced Nephrotoxicity in Mice

Masayuki Oda, Satoru Koyanagi, Yuuya Tsurudome, Takumi Kanemitsu, Naoya Matsunaga and Shigehiro Ohdo
Molecular Pharmacology May 2014, 85 (5) 715-722; DOI: https://doi.org/10.1124/mol.113.089805
Masayuki Oda
Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
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Satoru Koyanagi
Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
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Yuuya Tsurudome
Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
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Takumi Kanemitsu
Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
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Naoya Matsunaga
Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
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Shigehiro Ohdo
Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
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Abstract

Cisplatin, cis-diamminedichloro-platinum (CDDP), is a widely used anticancer agent, the clinical applications of which have been limited by severe nephrotoxicity. Although dosing time–dependent differences in CDDP-induced nephrotoxicity have been reported in both humans and laboratory animals, the underlying mechanism remains unknown. In the present study, we investigated the molecular mechanism for the dosing-time dependency of the nephrotoxic effect of CDDP in mice. CDDP-induced nephrotoxicity was significantly attenuated by injecting CDDP at times of the day when its renal clearance was enhanced. The dosing-time dependency of the nephrotoxic effect was parallel to that of CDDP incorporation into renal DNA. Two types of transporters, organic cation transporter 2 (OCT2, encoded by Slc22a2) and multidrug and toxin extrusion 1 (MATE1, encoded by Slc47a1), are responsible for the renal excretion of CDDP. The expression of OCT2, but not MATE1, exhibited a significant time-dependent oscillation in the kidneys of mice. The circadian expression of OCT2 was closely related to the dosing-time dependency of CDDP incorporation into renal DNA. Molecular components of the circadian clock regulated the renal expression of Slc22a2 mRNA by mediating peroxisome proliferator–activated receptor-α, which resulted in rhythmic oscillations in OCT2 protein levels. These findings indicate a clock-regulated mechanism of dosing time–dependent changes in CDDP-induced nephrotoxicity and also suggest a molecular link between the circadian clock and renal xenobiotic excretion.

Footnotes

    • Received September 24, 2013.
    • Accepted February 24, 2014.
  • This work was supported by a Grant-in-Aid for Scientific Research on Innovative Areas [25136716 to S.O.]; a Grant-in-Aid for Scientific Research (A) [25253038 to S.O.]; a Grant-in-Aid for Challenging Exploratory Research [25670079 to S.O.]; and a Grant-in-Aid for Scientific Research (B) [24390149 to S.K.] from Japan Society for the Promotion of Science.

  • dx.doi.org/10.1124/mol.113.089805.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 85 (5)
Molecular Pharmacology
Vol. 85, Issue 5
1 May 2014
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Research ArticleArticle

Circadian Regulation of Cisplatin-Induced Nephrotoxicity

Masayuki Oda, Satoru Koyanagi, Yuuya Tsurudome, Takumi Kanemitsu, Naoya Matsunaga and Shigehiro Ohdo
Molecular Pharmacology May 1, 2014, 85 (5) 715-722; DOI: https://doi.org/10.1124/mol.113.089805

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Research ArticleArticle

Circadian Regulation of Cisplatin-Induced Nephrotoxicity

Masayuki Oda, Satoru Koyanagi, Yuuya Tsurudome, Takumi Kanemitsu, Naoya Matsunaga and Shigehiro Ohdo
Molecular Pharmacology May 1, 2014, 85 (5) 715-722; DOI: https://doi.org/10.1124/mol.113.089805
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