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Journal of Lipid Research, Vol. 49, 1477-1487, July 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Decreased iPLA₂ expression induces lipid peroxidation and cell death and sensitizes cells to oxidant-induced apoptosis^*

Gilbert R. Kinsey^1,*, Jason L. Blum^1,*, Marisa D. Covington^*, Brian S. Cummings, Jane McHowat and Rick G. Schnellmann^2,*

^* Department of Pharmaceutical and Biomedical Sciences and Center for Cell Death, Injury, and Regeneration, South Carolina College of Pharmacy, Medical University of South Carolina, Charleston, SC 29425
Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, GA 30602
Department of Pathology, St. Louis University, St. Louis, MO 63104

^* This research was supported by National Institutes of Health Grant DK-62028 to R.G.S. G.R.K. was supported by a training grant from the National Institute of Environmental Health Sciences, National Institutes of Health (Grant T32 ES-012878), and J.L.B. was supported by an individual National Institutes of Health National Research Service Award training fellowship (Grant F32 DK-081267). The Medical University of South Carolina animal facilities were funded by National Institutes of Health Grant C06 RR-015455. The data presented here are solely the responsibility of the authors and do not represent the official views of the National Institutes of Health.

Published, JLR Papers in Press, April 8, 2008.

¹ G. R. Kinsey and J. L. Blum contributed equally to this work.

² To whom correspondence should be addressed. e-mail: schnell{at}musc.edu

Our previous studies showed that renal proximal tubular cells (RPTC) express Ca²⁺-independent phospholipase A₂ (iPLA₂) in endoplasmic reticulum (ER) and mitochondria and that iPLA₂ prevents and/or repairs lipid peroxidation induced by oxidative stress. Our present studies determined the importance of iPLA₂ in mitochondrial and cell function using an iPLA₂-specific small hairpin ribonucleic acid (shRNA) adenovirus. iPLA₂ expression and activity were decreased in the ER by 24 h and in the mitochondria by 48 h compared with scrambled shRNA adenovirus-treated cells. Lipid peroxidation was elevated by 2-fold at 24 h and remained elevated through 72 h in cells with decreased iPLA₂. Using electrospray ionization-mass spectrometry, primarily phosphatidylcholines and phosphatidylethanolamines were increased in iPLA₂-shRNA-treated cells. At 48 h after exposure to the iPLA₂ shRNA, uncoupled oxygen consumption was inhibited by 25% and apoptosis was observed at 72 and 96 h. RPTC with decreased iPLA₂ expression underwent apoptosis when exposed to a nonlethal concentration of the oxidant tert-butyl hydroperoxide (TBHP). Exposure of control cells to a nonlethal concentration of TBHP induced iPLA₂ expression in RPTC. These results suggest that iPLA₂ is required for the prevention and repair of basal lipid peroxidation and the maintenance of mitochondrial function and viability, providing further evidence for a cytoprotective role for iPLA₂ from oxidative stress.

Supplementary key words Ca²⁺-independent phospholipase A₂ • renal proximal tubular cells • mitochondria

Abbreviations: BEL, bromoenol lactone; DAPI, 4',6-diamidino-2-phenylindole; ER, endoplasmic reticulum; FCCP, carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone; iPLA₂, Ca²⁺-independent phospholipase A₂; MPT, mitochondrial permeability transition; PI, propidium iodide; PLA₂, phospholipase A₂; QO₂, oxygen consumption; RCM, renal cortex mitochondria; RPTC, renal proximal tubular cell; TBARS, thiobarbituric acid-reactive substances; TBHP, tert-butyl hydroperoxide

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