Renal organic cation transporters mediated cadmium-induced nephrotoxicity

The involvement of renal organic cation transporters (OCTs) in cadmium transport was investigated in Chinese hamster ovary (CHO-K1) cells stably and singly transfected with rabbit (rb)OCT1 and rbOCT2, in murine isolated renal proximal tubule, and in intact kidney following bilateral ureteral ligation of rat. Cadmium inhibited uptake of [3H]-tetraethylammonium (TEA), a substrate of rbOCT1 and rbOCT2, via both transporters with half maximal inhibitory concentration (IC50) of cadmium for rbOCT1- and rbOCT2-mediated TEA uptake of 96 ± 5 μM and 207 ± 12 μM, respectively. Cadmium similarly inhibited [3H]-TEA uptake in isolated non perfused renal proximal tubules. Cadmium accumulation in the transfected CHO-K1 cells was significantly higher than that of parent cells and this could be attenuated by TEA. In addition, cadmium accumulation in whole kidney was also reduced by TEA administration. Furthermore, exposure of the rbOCT1- and rbOCT2-expressing CHO-K1 cells to cadmium led to cytotoxicity, which could be prevented by TEA treatment. Taken together, this study provides for the first time, evidence showing OCT1 and OCT2 mediating cadmium transport across the basolateral membrane into the renal proximal tubular cells.