J. Lipid Res.
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Originally published In Press as doi:10.1194/jlr.M800030-JLR200 on April 8, 2008

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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{gamma} expression induces lipid peroxidation and cell death and sensitizes cells to oxidant-induced apoptosis*

Gilbert R. Kinsey1,*, Jason L. Blum1,*, Marisa D. Covington*, Brian S. Cummings{dagger}, Jane McHowat§ and Rick G. Schnellmann2,*

* 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
{dagger} 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{gamma} (iPLA2{gamma}) in endoplasmic reticulum (ER) and mitochondria and that iPLA2{gamma} prevents and/or repairs lipid peroxidation induced by oxidative stress. Our present studies determined the importance of iPLA2{gamma} in mitochondrial and cell function using an iPLA2{gamma}-specific small hairpin ribonucleic acid (shRNA) adenovirus. iPLA2{gamma} 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{gamma}. Using electrospray ionization-mass spectrometry, primarily phosphatidylcholines and phosphatidylethanolamines were increased in iPLA2{gamma}-shRNA-treated cells. At 48 h after exposure to the iPLA2{gamma} shRNA, uncoupled oxygen consumption was inhibited by 25% and apoptosis was observed at 72 and 96 h. RPTC with decreased iPLA2{gamma} 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{gamma} expression in RPTC. These results suggest that iPLA2{gamma} 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{gamma} 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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