Circadian Dependence of Subacute Renal Toxicity of Cadmium

ABSTRACT Cadmium (Cd) is an environmentally toxic metal that accumulates in kidneys and induces renal injury. Although oxidative stress and inflammation are recognized as contributors to Cd‐induced nephrotoxicity, emerging evidence suggests that circadian rhythms may also influence toxic responses. We have previously demonstrated that Cd‐induced acute hepatotoxicity varies drastically depending on the timing of exposure to Cd. However, it remains unclear whether the chronotoxicity of Cd is also observed in the kidneys. In the present study, we investigated diurnal variations in Cd‐induced nephrotoxicity in mice using a subacute exposure model. Mice were orally administered CdCl 2 (4 mg/kg) for 2 weeks during the light phase (zeitgeber time [ZT] 6) or dark phase (ZT18). ZT6 administration significantly increased the renal levels of neutrophil gelatinase‐associated lipocalin, and kidney injury molecule‐1 significantly increased. In addition, urinary N‐acetyl‐β‐D‐glucosaminidase level, β2‐microglobulin level, and renal apoptosis were elevated in Cd‐administrated mice at ZT6. These toxic effects were not observed in the group of ZT18 administration. Our results indicate a novel link between Cd‐induced renal toxicity and administration time and suggest that circadian mechanisms may be an important determinant of susceptibility to environmental nephrotoxicants.