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Nuclear Factor κB Activity Determines the Sensitivity of Kidney Epithelial Cells to Apoptosis: Implications for Mercury-Induced Renal Failure
Nuclear factor kappa B (NF-κB) is a thiol-dependent transcriptional factor that promotes cell survival and protects cells from apoptotic stimuli. Numerous studies have demonstrated increased sensitivity to apoptosis associated with inhibition of NF-κB activation in various cell types. We have previo...
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Published in: | Toxicological sciences 2004-11, Vol.82 (1), p.114-123 |
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Main Authors: | , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Online Access: | Get full text |
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Summary: | Nuclear factor kappa B (NF-κB) is a thiol-dependent transcriptional factor that promotes cell survival and protects cells from apoptotic stimuli. Numerous studies have demonstrated increased sensitivity to apoptosis associated with inhibition of NF-κB activation in various cell types. We have previously demonstrated that mercuric ion (Hg2+), one of the strongest thiol-binding agents known, impairs NF-κB activation and DNA binding at low μM concentrations in kidney epithelial cells. In the present studies we investigated the hypothesis that inhibition of NF-κB activation by Hg2+ and other selective NF-κB inhibitors would increase the sensitivity of kidney epithelial (NRK52E) cells to apoptogenic agents to which these cells are normally resistant. Fewer than 10% of untreated cells in culture were found to be apoptotic when evaluated by DNA fragmentation (TUNEL) assay. Treatment of cells with Hg2+ in concentrations up to 5 μM or with tumor necrosis factor-α (TNF) (300 units/ml) did not significantly increase the proportion of apoptotic cells, compared with untreated controls. However, when TNF was given following Hg2+ pretreatment (0.5 to 5 μM for 30 min), the proportion of cells undergoing apoptosis increased by 2- to 6-fold over that seen in untreated controls. Kidney cells pretreated with specific NF-κB inhibitors (Bay11-7082 or SN50) prior to TNF also showed a significant increase in apoptosis. Increased sensitivity to apoptotic cell death following these treatments was significantly attenuated in cells transfected with a p65 expression vector. In studies in vivo, rats pretreated by intraperitoneal injection with Hg2+ (0.75 mg/kg) 18 h prior to administration of bacterial lipopolysaccharide (LPS) (10 mg/kg) displayed impaired NF-κB activation and an increased mitochondrial cytochrome c release in kidney cortical cells. These findings are consistent with the view that prevention of NF-κB activity in vitro or in vivo enhances the sensitivity of kidney cells to apoptotic stimuli to which these cells are otherwise resistant. Since apoptosis is known to play a seminal role in the pathogenesis of renal failure caused by toxicant injury to tubular cells, the present findings suggest that inhibition of NF-κB activity may define a molecular mechanism underlying the pathogenesis of Hg2+ toxicity in kidney cells. |
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ISSN: | 1096-6080 1096-0929 |
DOI: | 10.1093/toxsci/kfh236 |