TY - JOUR T1 - Renal Circadian Clock Regulates the Dosing-time Dependency OF Cisplatin-induced Nephrotoxicity in Mice JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.113.089805 SP - mol.113.089805 AU - Masayuki Oda AU - Satoru Koyanagi AU - Yuuya Tsurudome AU - Takumi Kanemitsu AU - Naoya Matsunaga AU - Shigehiro Ohdo Y1 - 2014/02/24 UR - http://molpharm.aspetjournals.org/content/early/2014/02/24/mol.113.089805.abstract N2 - 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 (PPARα), 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. ER -