Journal Article

The Role of Endoplasmic Reticulum Ca<sup>2+</sup>-Independent Phospholipase A<sub>2</sub>γ in Oxidant-Induced Lipid Peroxidation, Ca<sup>2+</sup> Release, and Renal Cell Death

Andre C. Eaddy, Brian S. Cummings, Jane Mchowat and Rick G. Schnellmann

in Toxicological Sciences

Volume 128, issue 2, pages 544-552
Published in print August 2012 | ISSN: 1096-6080
Published online May 2012 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfs175
The Role of Endoplasmic Reticulum Ca2+-Independent Phospholipase A2γ in Oxidant-Induced Lipid Peroxidation, Ca2+ Release, and Renal Cell Death

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Oxidant-induced lipid peroxidation and cell death are major components of ischemia/reperfusion and toxicant injury. Our previous studies showed that renal proximal tubular cells (RPTCs) express Ca2+-independent phospholipase A2γ (iPLA2γ) in endoplasmic reticulum (ER) and mitochondria and that iPLA2γ is cytoprotective. Our present studies reveal the role of ER-iPLA2γ in oxidant-induced ER lipid peroxidation, Ca2+ release, and cell death. Oxidant tert-butyl hydroperoxide (TBHP) caused ER lipid peroxidation and Ca2+ release in isolated rabbit kidney cortex microsomes. ER-iPLA2γ inhibition, using bromoenol lactone (BEL), potentiated both oxidant-induced ER lipid peroxidation and Ca2+ release. Assessment of fatty acids using electrospray ionization-mass spectrometry revealed that ER-iPLA2γ mediates the TBHP-induced release of arachidonic acid (20:4), linoleic acid (18:2), and their oxidized forms (18:2-OH, 18:2-OOH, 20:4-OH, 20:4-OOH, 20:4-(OH)3. iPLA2γ inhibition also accelerated oxidant-induced ER Ca2+ release in RPTC. Depletion of ER Ca2+ stores in RPTC with thapsigargin, an ER Ca2+ pump inhibitor, prior to TBHP exposure reduced necrotic cell death and blocked the potentiation of TBHP-induced necrotic cell death by BEL. Together, these data provide strong evidence that ER-iPLA2γ protects renal cells from oxidant-induced necrotic cell death by releasing unsaturated and/or oxidized fatty acids from ER membranes, thereby preserving ER membrane integrity and preventing ER Ca2+ release.

Keywords: lipid peroxidation; phospholipase A2; Ca2+ release; necrotic cell death.

Journal Article.  5767 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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