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 e...

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Bibliographic Details
Published in:Toxicological sciences 2004-08, Vol.80 (2), p.358-366
Main Authors: Somji, Seema, Garrett, Scott H., Sens, Mary Ann, Gurel, Volkan, Sens, Donald A.
Format: Article
Language:English
Subjects:
apoptosis
Apoptosis - drug effects
cadmium
Cadmium - toxicity
Caspase 3
Caspases - metabolism
Cell Death - drug effects
Cell Line
Cell Survival - drug effects
DNA - genetics
Fluorescent Dyes
Humans
Indoles
Isomerism
kidney
Kidney Tubules, Proximal - drug effects
Kidney Tubules, Proximal - pathology
L-Lactate Dehydrogenase - metabolism
metallothionein
Necrosis
nephrotoxicity
Nerve Tissue Proteins - biosynthesis
Nerve Tissue Proteins - genetics
proximal tubule
Reverse Transcriptase Polymerase Chain Reaction
Transfection
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Summary: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.
ISSN:1096-6080
1096-0929
1096-0929
DOI:10.1093/toxsci/kfh158