Expression of metallothionein isoform 3 (MT-3) determines the choice between apoptotic or necrotic cell death in Cd+2-exposed human proximal tubule cells.
This laboratory has shown that the third isoform of metallothionein (MT-3) is expressed in the human kidney in situ, including the cells of the proximal tubule. A subsequent analysis of MT-3 expression in cell cultures derived from the human proximal tubule (HPT) demonstrated that mortal HPT cells expressed MT-3, while the HPV-immortalized HK-2 cells had no expression of MT-3. In the present study, the effect of MT-3 expression on Cd(+2)-induced cytotoxicity was determined by stable transfection of the MT-3 coding sequence into the HK-2 cell line. The results demonstrated that HK-2 cells stably transfected with MT-3 were more sensitive to the cytotoxic effects of Cd(+2). Furthermore, this increase in Cd(+2)-induced cytotoxicity was correlated to an alteration in the mechanism of cell death, being changed from an apoptotic mechanism in cells not expressing the MT-3 gene to a necrotic mechanism in cells expressing the MT-3 gene. The present study provides evidence that MT-3 could play a role in controlling the choice between apoptosis and necrosis in multiple epithelial cell types of the human kidney.
Somji
Seema
S
Department of Pathology, School of Medicine and Health Sciences, University of North Dakota, 501 N. Columbia Road, Grand Forks, North Dakota 58202-9037, USA.
Garrett
Scott H
SH
Sens
Mary Ann
MA
Gurel
Volkan
V
Sens
Donald A
DA
D017209:Apoptosis / Q000187:drug effects*; D002104:Cadmium / Q000633:toxicity*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000235:genetics; D005456:Fluorescent Dyes; D006801:Humans; D007211:Indoles; D007536:Isomerism; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000473:pathology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D000090023:Metallothionein 3; D009336:Necrosis; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
D005456:Fluorescent Dyes; D007211:Indoles; D000090023:Metallothionein 3; D009419:Nerve Tissue Proteins; D002104:Cadmium; C007293:DAPI; D004247:DNA; D007770:L-Lactate Dehydrogenase; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases