Reactive oxygen species are formed in the kidney directly or indirectly following toxicant exposures and other injuries. Oncosis (necrotic cell death) is a form of cell death characterized by ATP depletion, disruption of Ca2+ homeostasis, organelle and cellular swelling, and gross breakdown of the plasma membrane, and is one outcome of oxidant exposure. Consequently, oxidant-induced oncosis has been implicated in the pathogenesis of various acute nephropathies and nephrotoxic states. Phospholipase A2 (PLA2) isoforms have been proposed to play different roles in oxidant/toxicant-induced renal cell injury and oncosis, including acting as a phospholipid repair enzyme and playing a protective role during oxidant/toxicant injury. We have observed that inhibition of a Ca2+ independent PLA2 (iPLA2) prior to exposure to a number of diverse oxidants or cisplatin (a model nephrotoxicant) markedly potentiated oxidant- and cisplatin-induced renal proximal tubular cell (RPTC) oncosis. Further, the majority of iPLA2 activity and protein in RPTC was identified in the endoplasmic reticulum. These results suggest that an endoplasmic reticulum iPLA2 (m-iPLA2) may act as a phospholipid repair enzyme and attenuate cell injury and oncosis. The hypothesis to be tested by the proposed studies is that a novel m-iPLA2 plays a protective role and prevents oxidant/toxicant-induced RPTC oncosis.
The specific aims designed to test this hypothesis are: 1) Determine the selectivity of RPTC m-iPLA2 for phospholipids and their oxidized products, 2) Determine the role of m-iPLA2 in RPTC oncosis mediated by oxidants/toxicants, and 3) Identify the m-iPLA2 in RPTC. These integrated aims will result in the systematic examination of an important medical and scientific issue, the role of PLA2 in oxidant injury. While numerous studies have suggested that PLA2 contributes to cell injury, little effort has been expended to address the issue of a phospholipid repair mechanism. Successful completion of the proposed studies will result in this issue being addressed.
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