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

Abstract

Background/Aims: The present study was conducted to investigate the renal tubular handling of inorganic cadmium (Cd²⁺) by exposing primary human tubular cell cultures to physiologically relevant doses of cadmium chloride (CdCl₂). Furthermore, the cellular accumulation of Cd²⁺ 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 Cd²⁺ 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: Cd²⁺ accumulated into human tubular cells in a concentration- and time-dependent way. Furthermore, cellular accumulation of Cd²⁺ 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 CdCl₂ 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.