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Attenuation of nuclear factor kappa B (NF-kappaB) promotes apoptosis of kidney epithelial cells: a potential mechanism of mercury-induced nephrotoxicity.

By James S Woods, Francisco J Dieguez-Acuña, Maureen E Ellis, John Kushleika and P Lynne Simmonds

Abstract

Nuclear factor kappa B (NF-kappaB), a pleiotropic transcriptional factor that promotes cell survival and protects cells from apoptosis, requires reduced thiols at critical steps in its activation pathway. Mercuric ion (Hg(2+)), one of the strongest thiol-binding agents known, impairs NF-kappaB activation and transcriptional activity in normal rat kidney epithelial (NRK52E) cells at concentrations as low as 0.5 microM by binding to specific reduced thiol moieties in the NF-kappaB activation pathway. We hypothesized that prevention of NF-kappaB activation by Hg(2+) will increase the sensitivity of kidney cells to the apoptosis-inducing effects of other toxicants to which these cells are otherwise resistant by virtue of their NF-kappaB-activating capacity. Fewer than 5% of untreated kidney cells in culture (70-90% confluent) were found to be apoptotic when evaluated by DNA fragmentation (terminal deoxynucleotide transferase-mediated dUTP nick-end labeling) or flow cytometric DNA profile analyses. Hg(2+) (5 microM) treatment for 24 hr increased this proportion by 1.5- to 2-fold. Neither lipopolysaccharide (LPS) (1 microg/mL) nor tumor necrosis factor-alpha (TNF-alpha; 300 U/mL), both potent activators of NF-kappaB in kidney cells, significantly altered the proportion of apoptotic cells, compared with untreated controls, when applied without Hg(2+) pretreatment. However, when LPS or TNF-alpha was administered after Hg(2+) pretreatment (5 microM for 30 min), the proportion of cells undergoing apoptosis 22 hr later increased by 4- to 6-fold compared with untreated controls. In contrast, Hg(2+) pretreatment did not increase the amount of apoptosis caused by apoptosis-inducing agents that do not activate NF-kappaB (staurosporine, Fas ligand). These findings suggest that Hg(2+) enhances the sensitivity of kidney cells to apoptotic stimuli as a consequence of inhibition of NF-kappaB activity. Because apoptosis is known to play a key role in the pathogenesis of renal failure resulting from toxicant injury to proximal tubular cells, promotion of apoptosis via inhibition of NF-kappaB activity may define a novel molecular mechanism by which Hg(2+) toxicity is initiated in kidney cells

Topics: Research Article
Year: 2002
OAI identifier: oai:pubmedcentral.nih.gov:1241252
Provided by: PubMed Central

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Citations

  1. (2001). A constitutive cytoprotective pathway protects endothelial cells from lipopolysaccharideinduced apoptosis.
  2. (1999). Activation of NF-κ B in normal rat epithelial (NRK52E) cells is mediated via a redox-insensitive, calcium-dependent pathway.
  3. (2000). Apoptosis and nuclear factor κ B: a tale of association and dissociation.
  4. (1994). DNA content histogram and cell cycle analysis.
  5. (1984). Effect of prolonged saline loading on HgCl2-induced renal tubular damage.
  6. (1977). Effects of heavy metals and of deficiency of zinc on mortality rates in mice infected with encephalomyocarditis virus.
  7. (1973). Immunosuppression produced by lead, cadmium, and mercury.
  8. (2000). Inhibition of NF-κ B-DNA binding by mercuric ion: utility of the non-thiol reductant, tris(2-carboxyethyl)phosphine hydrochloride (TCEP), on detection of impaired NF-κ B-DNA binding by thioldirected agents. Toxicol In Vitro
  9. (1996). Mechanisms of apoptosis and its potential role in renal tubular epithelial cell injury.
  10. (2001). Mercuric ion attenuates nuclear factor-κ B activation and DNA binding in normal rat kidney epithelial cells: implications for mercury-induced nephrotoxicity.
  11. (2001). Mercury enhances susceptibility to murine leishmaniasis.
  12. (1982). Mitochondrial bioenergetics during the initiation of mercuric chlorideinduced renal injury. I: Direct effects of in vitro mercuric chloride on renal mitochondrial function.
  13. (1982). Mitochondrial bioenergetics during the initiation of mercuric chlorideinduced renal injury. II: Functional alterations of renal cortical mitochondria isolated after mercuric chloride treatment.
  14. (1993). N-terminal DNA-binding domains contribute to differential DNA-binding specificities of NF-κ B p50 and p65.
  15. (1999). New insights into the role of nuclear factor-κ B, a ubiquitous transcription factor, in the initiation of disease.
  16. (1984). Renal tubular lesions caused by mercuric chloride. Electron microscopic observations: degeneration of the pars recta.
  17. (2001). Role of apoptosis in renal tubular cells in acute renal failure: therapeutic implications.
  18. (1999). Signaling pathway activated during apoptosis of the prostate cancer cell line LNCaP: overexpression of caspase-7 as a new gene therapy strategy for the treatment of prostate cancer.
  19. (1993). Studies of Hg2+-induced H2O2 formation and oxidative stress in vivo and in vitro in rat kidney mitochondria.
  20. (2000). Tumor necrosis factor α prevents tumor necrosis receptor-mediated mouse hepatocyte apoptosis, but not Fas-mediated apoptosis: role of nuclear factor κ B. Hepatology 32:1272–1279
  21. (1977). Ultrastructural and biochemical changes in renal mitochondria following chronic oral methylmercury exposure: the relationship to renal function. Exp Mol Pathol

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