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.

The RPTEC/TERT1 Cell Line as an Improved Tool for In Vitro Nephrotoxicity Assessments

“…Studies examining responses of healthy primary human kidney epithelial cells to Cd exposure and other nephrotoxicants demonstrate findings similar to our results with the RPTEC/TERT1 cell line [45, 46]. In healthy primary human kidney cells, Cucu et al (2011) found that exposure to concentrations as low as 0.5 µM Cd significantly increased MTIA gene expression after 3 hours followed by a subsequent decline after 24 hours.…”

“…In healthy primary human kidney cells, Cucu et al (2011) found that exposure to concentrations as low as 0.5 µM Cd significantly increased MTIA gene expression after 3 hours followed by a subsequent decline after 24 hours. Additionally, significant increases in HMOX1 gene expression were demonstrated after exposure to 0.5 µM Cd indicating an oxidative stress response [45]. A study by Li et al (2013) compared healthy primary human kidney cells to two commonly used virally immortalized kidney cell lines, Human Kidney 2 (HK-2) and Lewis Lung Cancer-Porcine Kidney 1 (LLC-PK1).…”

Chronic cadmium exposure in vitro induces cancer cell characteristics in human lung cells

“…MMP-2 activity can also increase as a result of oxidant stress (Cucu et al, 2011). This is consistent with the present data indicating an oxidant stress response occurred with cadmium in CCT-LC cells.…”

“…Our present findings demonstrate that HO-1 and HIF-1A are both activated when the CCT-LC cells have acquired multiple tumor cell characteristics, potentially indicating adaptive responses to oxidative conditions. HO-1 is considered an antioxidative protein and is inducible by cadmium exposure (Cucu et al, 2011). HIF-1 can be induced by cadmium through production of reactive oxygen species (Jing et al, 2012).…”

The protective role of honey against cytotoxicity of cadmium chloride in mice

“…Amara et al (2011) and Singh et al (2007) mentioned that the damaged central nervous system and DNA or cancer progression appeared as consequences of Cd exposure. Cadmium also causes severe soft tissues and bone damages (Cucu et al, 2011;Ercal et al, 2001;Ersan et al, 2008). Cadmium is known to enhance the production of reactive oxygen species (ROS) (Liu et al, 2001).…”