This Article Order Full text via Infotrieve Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zager, R. A. Articles by Iwata, M. Search for Related Content PubMed PubMed Citation Articles by Zager, R. A. Articles by Iwata, M.

American Journal of Pathology, Vol 150, 735-745, Copyright © 1997 by American Society for Investigative Pathology

REGULAR ARTICLES

Inorganic fluoride. Divergent effects on human proximal tubular cell viability

RA Zager and M Iwata
Fred Hutchinson Cancer Research Center, Seattle, WA 98104, USA.

Fluoride (F) is a widely distributed nephrotoxin with exposure potentially resulting from environmental pollution and from fluorinated anesthetic use (eg, isoflurane). This study sought to characterize some of the subcellular determinants of fluoride cytotoxicity and to determine whether subtoxic F exposure affects tubular cell vulnerability to superimposed ATP depletion and nephrotoxic attack. Human proximal tubular cells (HK-2) were cultured with differing amounts of NaF (0 to 20 mmol/L, overlapping with clinically relevant intrarenal/urinary levels after fluorinated anesthetic use). After completing 24-hour exposures, cell injury was determined (vital dye uptake). Fluoride effects on cell deacylation ([3]H-C20:4 release) and PLA2 activity were also assessed. To determine whether subtoxic F exposure alters tubular cell susceptibility to superimposed injury, cells were exposed to subtoxic NaF doses for 0 to 24 hours and then challenged with simulated ischemia (ATP depletion plus Ca2+ overload) or a clinically relevant nephrotoxic insult (myoglobin exposure). NaF induced dose-dependent cytotoxicity (up to approximately 90% vital dye uptake and increased [3H]C20:4 release). Extracellular Ca2+ chelation (EGTA) and PLA2 inhibitor therapy (aristolochic acid, dibucaine, or mepacrine) each conferred significant protective effects. When subtoxic NaF doses were applied, partial cytosolic PLA2 depletion rapidly developed (approximately 85% within 3 hours, determined on cell extracts). These partially PLA2-depleted cells were markedly resistant to ATP depletion/Ca2+ ionophore injury and to myoglobin-induced attack (approximately 50% decrease in cell death). We conclude that 1) F induces dose-dependent cytotoxicity in cultured human proximal tubular cells, 2) this occurs, in part, via Ca(2+)- and PLA2-dependent mechanism(s), 3) partial cytosolic PLA2 depletion subsequently results, and 4) subtoxic fluoride exposure can acutely increase cell resistance to further attack. Reductions in cytosolic PLA2 activity could potentially contribute to this result.

This article has been cited by other articles:

				K. Kubota, D. H. Lee, M. Tsuchiya, C. S. Young, E. T. Everett, E. A. Martinez-Mier, M. L. Snead, L. Nguyen, F. Urano, and J. D. Bartlett Fluoride Induces Endoplasmic Reticulum Stress in Ameloblasts Responsible for Dental Enamel Formation J. Biol. Chem., June 17, 2005; 280(24): 23194 - 23202. [Abstract] [Full Text] [PDF]

				H. B. M. Lantum, R. B. Baggs, D. M. Krenitsky, and M. W. Anders Nephrotoxicity of Chlorofluoroacetic Acid in Rats Toxicol. Sci., December 1, 2002; 70(2): 261 - 268. [Abstract] [Full Text] [PDF]