Time-Dependent Changes in the Gene Expression Levels in the Mouse Kidney by Long-Term Exposure to Cadmium

Abstract

Cadmium (Cd) is an environmental hazardous heavy metal that causes renal dysfunction triggered by its toxicity to proximal tubular cells. Our previous study demonstrated that Cd changed the activities of various transcription factors (TFs) in the mouse kidney. In this study, we investigated whether long-term exposure to Cd affected the expression levels of downstream genes of these TFs. C57BL/6J female mice were fed chow containing 300 ppm Cd for 12 months. After 4, 8, and 12 months of Cd exposure, total RNA was extracted from the mouse kidney. The results confirmed that Cd exposure dramatically increased the expression of metallothionein-2 (Mt2) in the mouse kidney. Cd exposure increased the mRNA levels of Slc13a1, Vegfa, and Vegfb among the downstream genes regulated by Cd-activated TFs. Thy1 expression was decreased by Cd exposure, even though the upstream TF was activated by Cd. Furthermore, Cd exposure decreased the mRNA levels of Agtrap, Tert, Fgfr4, Foxq1, Abcb1b, Cd274, Pck1, and Egr1 among the downstream genes regulated by Cd-suppressed TFs. The expression of Pklr increased at 4-month Cd exposure, but decreased at 12-month exposure. Although our previous study indicated Cd exposure suppressed the retinoic acid receptor TF in the mouse kidney, in the present study, it was found that the downstream gene Tnfrsf10b was up-regulated by Cd exposure. For many of the genes whose expressions were affected by long-term Cd exposure, the relationship with Cd renal toxicity has not been reported so far. Our results may provide useful clues into the molecular mechanism of Cd renal toxicity.