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ToxSci Advance Access published online on May 5, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh158
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received February 9, 2004
Accepted April 22, 2004

Environmental Toxicology

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 1, Scott H. Garrett 1, Mary Ann Sens 1, Volkan Gurel 1, Donald A. Sens 2*

1 Department of Pathology, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58202
2 Department of Surgery, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58202

* To whom correspondence should be addressed. E-mail: dsens{at}medicine.nodak.edu.


  Abstract

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 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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