Renal circadian clock regulates the dosing-time dependency of cisplatin-induced nephrotoxicity in mice
| Autor: | Satoru Koyanagi, Yuuya Tsurudome, Takumi Kanemitsu, Masayuki Oda, Shigehiro Ohdo, Naoya Matsunaga |
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| Rok vydání: | 2014 |
| Předmět: |
inorganic chemicals
Male medicine.medical_specialty SLC47A1 Time Factors Organic Cation Transport Proteins Circadian clock Antineoplastic Agents Pharmacology Kidney Nephrotoxicity Mice Internal medicine Circadian Clocks medicine Animals Circadian rhythm neoplasms Cisplatin Mice Knockout Mice Inbred ICR biology Dose-Response Relationship Drug Kidney metabolism Organic Cation Transporter 2 Transporter female genital diseases and pregnancy complications Mice Inbred C57BL Endocrinology Renal physiology biology.protein NIH 3T3 Cells Molecular Medicine medicine.drug |
| Zdroj: | Molecular pharmacology. 85(5) |
| ISSN: | 1521-0111 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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