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ToxSci Advance Access originally published online on December 8, 2004
Toxicological Sciences 2005 84(1):120-128; doi:10.1093/toxsci/kfi048
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Toxicological Sciences vol. 84 no. 1 © Society of Toxicology 2005; all rights reserved.

Differential Induction of Podocyte Heat Shock Proteins by Prolonged Single and Combination Toxic Metal Exposure

Tad E. Eichler, B.S., Richard F. Ransom, Ph.D and William E. Smoyer, M.D.1

Pediatric Nephrology Division, Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109

Received October 13, 2004; accepted November 29, 2004

Cadmium, mercury, and arsenite are among the most abundant toxic metals (TM) in our environment, and chronic TM exposure leads to injury to the kidney's glomerular filtration barrier. The small heat shock protein hsp25, highly expressed in glomerular podocytes, is induced during development of experimental nephrotic syndrome, and hsp25 overexpression can protect cultured podocytes from injury. Because little is known about the effect of multiple TM on podocytes, we measured the response of cultured podocytes to prolonged exposures to single and multiple TM. Podocyte viability declined by approximately 50% after 3 days of treatment with 20 µM cadmium, mercury, or arsenite, and 40 µM of any of these metals was lethal. The toxicity of equimolar concentrations of two or all three metals in combination was significantly altered compared to individual metal treatments. Single TM treatments induced only modest increases in the amounts of hsp25, {alpha}B-crystallin, and inducible hsp70. Toxic metal combinations induced greater stress protein accumulation, especially arsenite + cadmium or arsenite + cadmium + mercury treatments, the TM mixtures with the lowest toxicity. All TM treatments caused a rapid and sustained increase in hsp25 phosphorylation. The intracellular accumulation of cadmium was greater and that of mercury was less in cells treated with TM combinations than in cells treated with a single TM. Our results showed that multiple TM effects on podocyte viability were neither additive nor synergistic and that induction of heat shock proteins correlated with increased resistance to TM injury, suggesting that induction of small heat shock proteins may play an important role in preventing TM-induced podocyte injury.

Key Words: cadmium; arsenite; mercury; Hsp25; Hsp70; {alpha}B-crystallin.


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T. Eichler, Q. Ma, C. Kelly, J. Mishra, S. Parikh, R. F. Ransom, P. Devarajan, and W. E. Smoyer
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