PT  - JOURNAL ARTICLE
AU  - Oda, Masayuki
AU  - Koyanagi, Satoru
AU  - Tsurudome, Yuuya
AU  - Kanemitsu, Takumi
AU  - Matsunaga, Naoya
AU  - Ohdo, Shigehiro
TI  - Renal Circadian Clock Regulates the Dosing-Time Dependency of Cisplatin-Induced Nephrotoxicity in Mice
AID  - 10.1124/mol.113.089805
DP  - 2014 May 01
TA  - Molecular Pharmacology
PG  - 715--722
VI  - 85
IP  - 5
4099  - http://molpharm.aspetjournals.org/content/85/5/715.short
4100  - http://molpharm.aspetjournals.org/content/85/5/715.full
SO  - Mol Pharmacol2014 May 01; 85
AB  - 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.