Arachidonic acid release in renal proximal tubule cell injuries and death.
Arachidonic acid release and the effect of phospholipase inhibitors on various types of cell injuries and death to rabbit renal proximal tubule suspensions were determined. Proximal tubules were exposed to the mitochondrial inhibitor antimycin A (0.1 microM), the protonophore carbonyl cyanide p-trifluoromethoxyphenylhydrazone (1 microM FCCP), the oxidant tert-butyl hydroperoxide (0.5 mM TBHP), or the calcium ionophore ionomycin (5 microM) in the absence or presence of the putative phospholipase inhibitors dibucaine, mepacrine, chlorpromazine, or U-26384. The phospholipase inhibitors had no effect on the proximal tubule lactate dehydrogenase (LDH) release (a marker of cell death) produced by FCCP, antimycin A, or ionomycin after 1,2, or 2 hours of exposure, respectively. Only dibucaine and mepacrine decreased LDH release in TBHP-treated proximal tubules without decreasing TBHP-induced lipid peroxidation. Antimycin A and ionomycin did not release arachidonic acid from proximal tubules prelabeled with [1-14C] arachidonic acid. In contrast, TBHP released arachidonic acid from proximal tubules prior to the onset of cell death, and dibucaine and mepacrine decreased the TBHP-induced release. Thus, phospholipase inhibitors were cytoprotective in those injuries that produced arachidonic acid release. These results suggest that arachidonic acid release and phospholipase A2 activation play a contributing role in oxidant-induced renal proximal tubule cell injury and death but not in mitochondrial inhibitor- or calcium ionophore-induced proximal tubule cell injury and death.
Department of Physiology and Pharmacology, College of Veterinary Medicine, Athens, GA.
R G
RG
Schnellmann
X
X
Yang
J B
JB
Carrick
D000818:Animals; D000968:Antimycin A / Q000633:toxicity; D016718:Arachidonic Acid / Q000378:metabolism*; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D005260:Female; D066298:In Vitro Techniques; D015759:Ionomycin / Q000494:pharmacology; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D010545:Peroxides / Q000633:toxicity; D010740:Phospholipases / Q000037:antagonists & inhibitors; D011817:Rabbits; D017382:Reactive Oxygen Species / Q000633:toxicity; D020122:tert-Butylhydroperoxide
D010545:Peroxides; D017382:Reactive Oxygen Species; D016718:Arachidonic Acid; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D015759:Ionomycin; D000968:Antimycin A; D020122:tert-Butylhydroperoxide; D007770:L-Lactate Dehydrogenase; D010740:Phospholipases