Cadmium-induced cytosolic Ca2+ elevation and subsequent apoptosis in renal tubular cells.
Cadmium (Cd2+) is an industrial and environmental metal. The effect of Cd2+ on intracellular free-Ca2+ levels ([Ca2+](i)) and viability in Madin Darby canine kidney cells was explored. Cd2+increased [Ca2+](i) in a concentration-dependent manner with an EC50 of 85 microM. Cd2+-induced Mn2+ entry demonstrated Ca2+ influx. Removal of extracellular Ca2+ decreased the [Ca2+](i) signal by 60%. The [Ca2+](i) signal was inhibited by La3+ but not by L-type Ca2+ channel blockers. In Ca2+-free medium, Cd2+-induced [Ca2+]i signal was abolished by pre-treatment with 1 microM thapsigargin (an endoplasmic reticulum Ca2+pump inhibitor) and 2 microM carbonylcyanide m-chlorophenylhydrazone (CCCP; a mitochondrial uncoupler). Cd2+-induced Ca2+ release was not altered by inhibition of phospholipase C. At concentrations between 10 and 100 microM, Cd2+killed cells in a concentration-dependent manner. The cytotoxic effect of 100 microM Cd2+was reversed by pre-chelating cytosolic Ca2+with BAPTA. Cd2+-induced apoptosis was demonstrated by propidium iodide. Collectively, this study shows that Cd2+ induced a [Ca2+](i) increase in Madin Darby canine kidney cells via evoking Ca2+ entry through non-selective Ca2+ channels, and releasing stored Ca2+ from endoplasmic reticulum and mitochondria in a phospholipase C-independent manner.
Pathology and Laboratory Medicine Department, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
Jeng-Hsien
JH
Yeh
Chorng-Chih
CC
Huang
Mei-Yin
MY
Yeh
Jyh-Seng
JS
Wang
Jenn-Kuen
JK
Lee
Chung-Ren
CR
Jan
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D019187:Cadmium Compounds / Q000633:toxicity*; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003600:Cytosol / Q000187:drug effects* / Q000378:metabolism; D004285:Dogs; D004785:Environmental Pollutants / Q000633:toxicity*; D007684:Kidney Tubules / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008274:Magnesium / Q000378:metabolism; D010738:Type C Phospholipases / Q000378:metabolism
D019187:Cadmium Compounds; D002121:Calcium Channel Blockers; D004785:Environmental Pollutants; D010738:Type C Phospholipases; D008274:Magnesium; D002118:Calcium