ToxSci Advance Access originally published online on February 14, 2006
Toxicological Sciences 2006 91(1):299-308; doi:10.1093/toxsci/kfj131
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Cadmium-Induced Apoptosis in Rat Kidney Epithelial Cells Involves Decrease in Nuclear Factor-Kappa B Activity
Department of Biomedical and Pharmaceutical Sciences and Center for Molecular Toxicology, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island 02881
Received November 9, 2005; accepted January 30, 2006
Renal epithelial cells undergo apoptosis upon exposure to cadmium (Cd). Transcription factors, such as nuclear factor-kappa B (NF-
B), mediate the expression of a number of genes involved in apoptosis. The present study was designed to examine the involvement of this transcription factor in Cd-induced apoptosis. Rat kidney proximal tubular epithelial cells, NRK-52E, were incubated with up to 20µM CdCl2 in serum-free medium for 5 h followed by incubation in serum-containing medium (without Cd) for an additional 12 h. The cells accumulated 582 ± 19 ng Cd/mg protein after 5-h exposure to 20µM Cd. As a result of Cd exposure, the DNA-binding activity of the p65 subunit of NF-B was decreased in a concentration- and time-dependent manner. The activity of tumor necrosis factor-
–induced inhibitor of kappa B (IB) kinase was also inhibited by Cd. In addition, the phosphorylation of IB- and NF-B p65, as well as the levels of NF-B target gene products, cIAP-1 and cIAP-2, were reduced. Pretreatment of the cells with the antioxidant U83836E or butylated hydroxytoluene preserved the DNA-binding activity and blocked the Cd-induced decease in IB- phosphorylation. Cd exposure caused the activation of caspase-3, -7, and -9 and DNA fragmentation. By flow cytometry, 14.6 and 30.5% apoptosis was detected at 6 and 12 h after stopping the Cd exposure. Overexpression of NF-B p65 by transient transfection protected the cells from the Cd-induced apoptosis. Conversely, attenuation of NF-B activity by pretreatment with SN50, an NF-B nuclear translocation inhibitor, potentiated apoptosis. These results suggest that Cd-induced apoptosis involves suppression of NF-B activity which may be mediated by oxidative stress.
Key Words: cadmium; nuclear factor-kappa B (NF-B); IKK; IB; IAPs; apoptosis; kidney; epithelial cells; oxidative stress.
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