BCRP/ABCG2 Transporter Regulates Accumulation of Cadmium in Kidney Cells: Role of the Q141K Variant in Modulating Nephrotoxicity.

ABSTRACT

Exposure to the environmental pollutant cadmium is ubiquitous, as it is present in cigarette smoke and the food supply. Over time, cadmium enters and accumulates in the kidneys, where it causes tubular injury. The breast cancer resistance protein (BCRP, ATP-Binding Cassette G2 ABCG2) is an efflux transporter that mediates the urinary secretion of pharmaceuticals and toxins. The ABCG2 genetic variant Q141K exhibits altered membrane trafficking that results in reduced efflux of BCRP substrates. Here, we sought to 1) evaluate the in vitro and in vivo ability of BCRP to transport cadmium and protect kidney cells from toxicity and 2) determine whether this protection is impaired by the Q141K variant. Cadmium concentrations, cellular stress, and toxicity were quantified in human embryonic kidney 293 cells expressing an empty vector (EV), BCRP wild-type (WT), or variant (Q141K) gene. Treatment with CdCl2 resulted in greater accumulation of cadmium and apoptosis in EV cells relative to WT cells. Exposure to CdCl2 induced expression of stress-related genes and proteins including MT-1A/MT-2A, NAD(P)H quinone dehydrogenase 1, and heme oxygenase-1 to a higher extent in EV cells compared with WT cells. Notably, the Q141K variant protected against CdCl2-induced activation of stress genes and cytotoxicity, but this protection was to a lesser magnitude than observed with WT BCRP. Lastly, concentrations of cadmium in the kidneys of Bcrp knockout mice were 40% higher than in WT mice, confirming that cadmium is an in vivo substrate of BCRP. In conclusion, BCRP prevents the accumulation of cadmium and protects against toxicity, a response that is impaired by the Q141K variant. SIGNIFICANCE STATEMENT The breast cancer resistance protein transporter lowers cellular accumulation of the toxic heavy metal cadmium. This protective function is partially attenuated by the Q141K genetic variant in the ABCG2 gene.