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ToxSci Advance Access originally published online on May 5, 2004
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Toxicological Sciences 80, 358-366 (2004)
Toxicological Sciences vol. 80 no. 2 © Society of Toxicology 2004; all rights reserved.

Expression of Metallothionein Isoform 3 (MT-3) Determines the Choice between Apoptotic or Necrotic Cell Death in Cd+2-Exposed Human Proximal Tubule Cells

Seema Somji*, Scott H. Garrett*, Mary Ann Sens*, Volkan Gurel* and Donald A. Sens{dagger},1

* Department of Pathology and {dagger} Department of Surgery, School of Medicine and Health Sciences, University of North Dakota, 501 N. Columbia Road, Grand Forks, North Dakota 58202-9037

Received February 9, 2004; accepted April 22, 2004

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.

Key Words: cadmium; proximal tubule; nephrotoxicity; metallothionein; apoptosis; necrosis; kidney.


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