Toxicological Sciences vol. 82 no. 2 © Society of Toxicology 2004; all rights reserved.
TOXICOLOGICAL HIGHLIGHT |
Altered Nuclear Factor Kappa-B Activity and Mercury-Induced Kidney Tubule Cell Apoptosis: Implications for Renal Failure
Division of Toxicology, Agency Toxic Substances and Disease Registry, 1600 Clifton Road NE, MS F-32, Atlanta, Georgia 30333
Received October 11, 2004; accepted October 13, 2004
The article highlighted in this issue is ‘Nuclear Factor 
B Activity Determines the Sensitivity of Kidney Epithelial Cells to Apoptosis: Implications for Mercury-Induced Renal Failure,’ by Francisco J. Dieguez-Acuña, William W. Polk, Maureen E. Ellis, P. Lynne Simmonds, John V. Kushleika, and James S. Woods. This article appeared in the November issue (pp. 114–123).
The great power of understanding mechanisms of cell injury and cell death rests in providing valuable insights into how drugs and/or chemical agents may interact with target cell populations to produce clinical disease (Fowler, 1987
). Once these insights are understood, they may be used to prevent the insidious onset of damage to major target organ systems from chemical interactions before it occurs. The present article by Dieguez-Acuña et al. is an excellent example of how basic mechanistic information regarding altered regulation of a major molecular factor nuclear factor kappa B (NFkB) by mercury in combination with other molecular elements, such as TNF and Bay 11-7082 or SN50, may influence the expression of apoptosis in renal tubule cells both in vivo and in vitro. These findings have both basic scientific and applied scientific implications.
On the basic scientific level, the in vitro data reported in this article demonstrate a marked increase in the development of apoptosis by the TUNEL assay in NRK52E cells when TNF was administered to cell cultures following incubation with Hg2+ over a 0.5–5 µM concentration range for 30 min. This treatment protocol resulted in a 2–6 fold increase in apoptotic cells over controls. These effects were not observed with either TNF or Hg2+ (5 µM) alone clearly indicating an interactive effect between these two biologically active agents. Similar results were observed when the kidney cells were treated with Hg2+ in combination with two specific inhibitors of NFkB (Bay11-7082 and SN50) suggesting that a number of chemical agents which inhibit NFkB may produce similar increases in apoptosis in renal tubule cells with concomitant exposure to classical nephrotoxic agents such as Hg2+.
In vivo studies using rats injected with 0.75 mg/kg and bacterial lipopolysacharide (LPS), which is an inhibitor of NFkB, also showed inhibition of NFkB activation and increased cytochrome c release from renal cortical cells. Taken together, the results of the in vitro and in vivo studies are consistent with the view that chemical factors which inhibit NFkB will predispose renal tubule cells to the onset of apoptosis.
Activation of NFkB is recognized (Royds et al., 1998; Yi et al., 2002) as being a central molecular regulatory element in the development of apoptosis by a number of physical (radiation, hypoxia) and chemical (Hg2+) agents which act through the intracellular formation of reactive oxygen species (ROS) (Nath et al., 1996). The results of the present article add to this knowledge base by illustrating that the complexity of molecular regulatory factors, which are known from the works of others to regulate NFkB, which include HSP 25/27 (Samali and Cotter, 1996; Samali et al., 2001; Yi et al., 2002) and metallothionein (Butcher et al., 2004) may be overridden or bypassed by concomitant exposure to a number of distinct drug or chemical agents thereby permitting the induction of apoptosis. As noted in the present article, development of apoptosis in renal tubule cells via inhibition of NFkB following exposure to mercury in combination of interactive factors may ultimately lead to renal failure in vivo. The potential insights from this observation are also important. From the applied or clinical perspective, renal failure or end stage renal disease (ESRD) is not a trivial matter either in terms of human suffering or the societal treatment costs of dealing with this common health problem. Clinical treatment of ESRD has an annual cost for dialysis and renal transplants on the order of $17.9 billion (National Kidney Foundation, 2003). While most of the patients receiving these treatments experienced ESRD from diseases such as diabetes, there are about 20% who develop ESRD from unknown causes (National Kidney Foundation, 2003). The possible roles of common nephrotoxic metals in combination with drugs and other chemicals that may alter susceptibility to induction of apoptosis in renal tubule cell are presently unknown but worthy of further study.
Altered regulation of the molecular signaling systems that control apoptotic pathways by combinations of drugs or mixtures of chemical agents is a relatively unstudied area of toxicology. This is, however, clearly a common situation of chemical exposure among persons taking multiple drugs that are cleared by the kidney, workers exposed to multiple chemical agents in the work environment, and the general public exposed to several nephrotoxic agents at Superfund sites. At present, we have a limited understanding of how exposure to multiple chemical agents may influence target organ systems such as the kidney over the course of a human lifetime. The article by Dieguez-Acuña et al. provides some useful mechanistic data on the consequences of how altered regulation of NFkB may influence susceptibility to development of apoptosis in renal tubule cell populations following exposure to Hg2+ over low to moderate dose ranges both in vitro and in vivo. As noted by the authors, ‘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 NFkB may define a molecular mechanism underlying the pathogenesis of Hg2+ toxicity in kidney cells.’ The findings of these studies have some interesting and broader implications for other classes of nephrotoxic drugs or chemical agents that include both metals/metalloids as well as organic chemicals. The present article should stimulate toxicological research on this question for a number of these agents. It is hence a very valuable contribution to the field of mechanisms of cell injury and cell death, which is of great current interest to modern toxicology.
NOTES
1 For correspondence via fax: (770) 488-4178. E-mail: bxf9{at}cdc.gov.
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