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ToxSci Advance Access originally published online on January 18, 2006
Toxicological Sciences 2006 90(2):392-399; doi:10.1093/toxsci/kfj106
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Single and Combination Toxic Metal Exposures Induce Apoptosis in Cultured Murine Podocytes Exclusively via the Extrinsic Caspase 8 Pathway

Tad Eichler*, Qing Ma{dagger}, Caitlin Kelly{dagger}, Jaya Mishra{dagger}, Samir Parikh{dagger}, Richard F. Ransom*, Prasad Devarajan{dagger} and William E. Smoyer*,1

* Pediatric Nephrology Division, C. S. Mott Children's Hospital, University of Michigan, Ann Arbor, Michigan 48109, and {dagger} Division of Nephrology & Hypertension, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229-3039

Received November 16, 2005; accepted January 10, 2006

Arsenite, cadmium, and mercury are among the most abundant toxic metals (TM) in the environment. Although the most common renal manifestation of TM toxicity is proximal tubular dysfunction, significant glomerular injury can also occur. We hypothesized that glomerular injury following TM exposure results from TM-induced apoptosis of podocytes. To test this hypothesis we examined the extent of apoptosis and the apoptotic pathways induced in cultured murine podocytes incubated for three days with arsenite, cadmium, or mercury, and with equimolar combinations of all three metals. Apoptosis was detected by DNA laddering, and the number of apoptotic nuclei determined by Tunel assay. Treatment for three days with each TM resulted in DNA laddering and induced a dose-dependent increase in apoptotic nuclei. In contrast, treatment with equimolar combinations of TM induced significantly fewer apoptotic nuclei than individual TM treatments. Apoptosis induced by each TM was associated with a significant (~400%) increase in caspase 8 activity, but no change in caspase 9 activity, and Western analyses revealed a marked up-regulation of Fas (~500%) and FADD (~300%) with no change in expression of Bax, Bcl-2, or Bcl-xL. Similar to the apoptotic response, combinations of TM induced less caspase 8 activity and Fas/FADD expression than individual TM treatments. Collectively, these results demonstrate that (1) TM induced apoptosis in cultured murine podocytes via the extrinsic Fas-FADD caspase 8 pathway, rather than the mitochondrial apoptotic pathway, and (2) combination TM exposure induced less apoptosis than individual TM, indicating an antagonistic rather than an additive or synergistic toxicity.

Key Words: apoptotic pathway; cadmium; mercury; arsenite.


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