Period3 transgenic mice attenuate cadmium-induced chronic renal toxicity associated with reduced Trpm7 expression

Cadmium is an environmentally toxic metal that accumulates in the kidneys and induces oxidative stress-mediated chronic renal injury. Several studies have reported that metal toxicity is modulated by clock genes, which are master regulators of circadian rhythms. However, the role of clock genes in cadmium-induced renal toxicity remains unclear. In this study, we investigated the relationship between cadmium exposure and clock gene expression and examined the protective roles of Period3 ( Per3 ), one of the several core circadian clock genes against cadmium-induced renal toxicity. Mice were chronically exposed to cadmium (100 ppm in drinking water) for up to 6 months, which resulted in progressive renal accumulation of the toxic metal and mild nephrotoxicity, as evidenced by the increased levels of plasma blood urea nitrogen and the renal injury markers kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and cleaved caspase-3. Among the clock genes examined, Per3 was the most persistently downregulated throughout the exposure period and therefore selected for further functional analyses. Notably, cadmium-induced renal dysfunction, tubular injury, and apoptosis were significantly attenuated in Per3- overexpressing transgenic mice, which also exhibited significantly reduced renal cadmium accumulation. Among the metal transporter genes examined, only transient receptor potential melastatin 7 ( Trpm7 ) was significantly downregulated in Per3 -overexpressing TG mice and MuRTE61 cells. These findings suggest that Per3 plays a protective role against cadmium-induced nephrotoxicity by attenuating oxidative stress-associated tubular injury and may reduce accumulation of the metal, at least in part, by suppressing Trpm7 expression. These results highlight a novel link between circadian clock regulation and metal-induced renal toxicity and suggest that circadian mechanisms may be important determinants of susceptibility to environmental nephrotoxicants.