The role of endoplasmic reticulum ca2+-independent phospholipase a2γ in oxidant-induced lipid peroxidation, ca2+ release, and renal cell death

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

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)544-552
Number of pages9
JournalToxicological Sciences
Volume128
Issue number2
DOIs
StatePublished - Aug 2012
Externally publishedYes

Keywords

  • Ca2+ release
  • Lipid peroxidation
  • Necrotic cell death.
  • Phospholipase A2

ASJC Scopus subject areas

  • Toxicology

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