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 timedependent 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. CDDPinduced 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-a, 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.

Aging increases the susceptibility of cisplatin-induced nephrotoxicity

“…It was demonstrated that CDDP was transported into proximal tubular cells through the basal transporters OCT2 (Franke et al 2010) and CTR1 (Pabla et al 2009) from plasma, and excreted into urine via MRP2 (Wen et al 2014) and MATE1 (Nakamura et al 2010) located at the apical membrane. Recently, Masayuki et al (Oda et al 2014) reported that the rhythmic oscillations of renal OCT2 protein levels by circadian clock was a possible mechanism of dosing time-dependent changes in CDDP-induced nephrotoxicity. In addition, drug interaction on and the genetic variations of CDDP transporters were also found in a relationship to CDDP-induced nephrotoxicity (Tanihara et al 2009; Iwata et al 2012; Zhang and Zhou 2012; Sprowl et al 2013).…”

Dosing‐time contributes to chronotoxicity of clofarabine in mice via means other than pharmacokinetics

“…Circadian rhythms are essential for maintaining behavior, endocrine, and other physiological activities in mammals, which are largely influenced by feeding activities and light–dark (LD) cycle. Importantly, this internal timekeeper system is also involved in the absorption, distribution, metabolism, and elimination of drugs in vivo [14]. As a result, chronotherapy has been increasingly developed and employed in cancer and other disease therapies [15].…”

Timing in drug absorption and disposition: The past, present, and future of chronopharmacokinetics

“…This drug is transported into renal cells by the organic cation transporter 2 (OCT2), which was less expressed during this period (ZT 18). Therefore, the lower nephrotoxicity of cisplatin in the dark phase is explained by its lower uptake into renal cells, caused by lower levels of OCT2 (Oda et al, 2014). Rhythmic oscillations of other transporters in the kidney have been investigated by Ando et al (2005), pointing towards higher mRNA levels of Abcc2 at ZT 12 in mouse (Figure 2).…”