Document Detail

Inorganic fluoride. Divergent effects on human proximal tubular cell viability.
MedLine Citation:
PMID:  9033286     Owner:  NLM     Status:  MEDLINE    
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.
R A Zager; M Iwata
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  The American journal of pathology     Volume:  150     ISSN:  0002-9440     ISO Abbreviation:  Am. J. Pathol.     Publication Date:  1997 Feb 
Date Detail:
Created Date:  1997-03-18     Completed Date:  1997-03-18     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  0370502     Medline TA:  Am J Pathol     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  735-45     Citation Subset:  AIM; IM    
Fred Hutchinson Cancer Research Center, Seattle, WA 98104, USA.
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MeSH Terms
Adenosine Triphosphate / deficiency
Calcium / metabolism
Cell Survival
Cells, Cultured
Enzyme Inhibitors / pharmacology
Extracellular Space / metabolism
Kidney Tubules, Proximal / cytology,  drug effects*,  physiology
Myoglobin / pharmacology
Phospholipases A / antagonists & inhibitors
Phospholipases A2
Sodium Fluoride / pharmacology*
Grant Support
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Myoglobin; 56-65-5/Adenosine Triphosphate; 7440-70-2/Calcium; 7681-49-4/Sodium Fluoride; EC 3.1.1.-/Phospholipases A; EC A2

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