Cadmium-induced Cytosolic Ca2+ Elevation and Subsequent Apoptosis in Renal Tubular Cells

Cadmium (Cd 2+ ) is an industrial and environmental metal. The effect of Cd 2+ on intracellular free-Ca 2+ levels ([Ca 2+ ] i ) and viability in Madin Darby canine kidney cells was explored. Cd 2+ increased [Ca 2+ ] i in a concentration-dependent manner with an EC 50 of 85 μM. Cd 2+ -induced Mn 2+ entry demonstrated Ca 2+ influx. Removal of extracellular Ca 2+ decreased the [Ca 2+ ] i signal by 60%. The [Ca 2+ ] i signal was inhibited by La 3+ but not by L-type Ca 2+ channel blockers. In Ca 2+ -free medium, Cd 2+ -induced [Ca 2+ ] i signal was abolished by pre-treatment with 1 μM thapsigargin (an endoplasmic reticulum Ca 2+ pump inhibitor) and 2 μM carbonylcyanide m-chlorophenylhydrazone (CCCP; a mitochondrial uncoupler). Cd 2+ -induced Ca 2+ release was not altered by inhibition of phospholipase C. At concentrations between 10 and 100 μM, Cd 2+ killed cells in a concentration-dependent manner. The cytotoxic effect of 100 μM Cd 2+ was reversed by pre-chelating cytosolic Ca 2+ with BAPTA. Cd 2+ -induced apoptosis was demonstrated by propidium iodide. Collectively, this study shows that Cd 2+ induced a [Ca 2+ ], increase in Madin Darby canine kidney cells via evoking Ca 2+ entry through non-selective Ca 2+ channels, and releasing stored Ca 2+ from endoplasmic reticulum and mitochondria in a phospholipase C-independent manner.