title: Renal circadian clock regulates the dosing-time dependency of cisplatin-induced nephrotoxicity in mice.
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.
authors.affiliation: Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Oda
authors.forename: Satoru
authors.initials: S
authors.lastname: Koyanagi
authors.forename: Yuuya
authors.initials: Y
authors.lastname: Tsurudome
authors.forename: Takumi
authors.initials: T
authors.lastname: Kanemitsu
authors.forename: Naoya
authors.initials: N
authors.lastname: Matsunaga
authors.forename: Shigehiro
authors.initials: S
authors.lastname: Ohdo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D057906:Circadian Clocks / Q000187:drug effects / Q000502:physiology*; D002945:Cisplatin / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D041681:NIH 3T3 Cells; D027701:Organic Cation Transport Proteins / Q000096:biosynthesis*; D000075102:Organic Cation Transporter 2; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; C491012:Slc22a2 protein, mouse; D002945:Cisplatin