Low Doses of Cadmium Chloride and Methallothionein-1-Bound Cadmium Display Different Accumulation Kinetics and Induce Different Genes in Cells of the Human Nephron

BACKGROUND/AIMS The present study was conducted to investigate the renal tubular handling of inorganic cadmium (Cd(2+)) by exposing primary human tubular cell cultures to physiologically relevant doses of cadmium chloride (CdCl(2)). Furthermore, the cellular accumulation of Cd(2+) was compared to that of metallothionein-1-bound Cd (Cd7MT-1). Finally, this study aimed to investigate the effect of the accumulation of Cd (both Cd(2+) and Cd7MT-1) in renal cells on the expression of genes relevant to nephrotoxic processes. METHODS Cd concentration was measured using atomic absorption spectrometry. mRNA expression was evaluated by quantitative real-time RT-PCR. RESULTS Cd(2+) accumulated into human tubular cells in a concentration- and time-dependent way. Furthermore, cellular accumulation of Cd(2+) was different from the cellular accumulation of Cd7MT-1, indicative for different uptake routes. Finally, mRNA expression of the genes encoding the anti-oxidative proteins metallothionein-1 (MT-1) and heme-oxygenase-1 (HO-1) as well as the pro-apoptotic Bcl-2-associated X protein (Bax) were upregulated by CdCl(2) and not by Cd7MT1. CONCLUSION In the presence of physiologically relevant Cd concentrations, tubular accumulation of the element in its inorganic form is different from that of Cd7MT-1. Furthermore, the tubular accumulation of inorganic Cd induces mRNA expression of genes of which the protein products may play a role in Cd-associated renal toxicity.