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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK062028-03
Application #
6710612
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Rys-Sikora, Krystyna E
Project Start
2002-03-15
Project End
2006-12-31
Budget Start
2004-02-01
Budget End
2006-12-31
Support Year
3
Fiscal Year
2004
Total Cost
$332,850
Indirect Cost
Name
Medical University of South Carolina
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Eaddy, Andre C; Cummings, Brian S; McHowat, Jane et al. (2012) The role of endoplasmic reticulum Ca2+-independent phospholipase a2ýý in oxidant-induced lipid peroxidation, Ca2+ release, and renal cell death. Toxicol Sci 128:544-52
Wills, Lauren P; Trager, Richard E; Beeson, Gyda C et al. (2012) The ?2-adrenoceptor agonist formoterol stimulates mitochondrial biogenesis. J Pharmacol Exp Ther 342:106-18
Wills, Lauren P; Schnellmann, Rick G (2011) Telomeres and telomerase in renal health. J Am Soc Nephrol 22:39-41
Eaddy, Andre C; Schnellmann, Rick G (2011) Visualization and quantification of endoplasmic reticulum Ca2+ in renal cells using confocal microscopy and Fluo5F. Biochem Biophys Res Commun 404:424-7
Blum, Jason L; Kinsey, Gilbert R; Monian, Prashant et al. (2011) Profiling of fatty acids released during calcium-induced mitochondrial permeability transition in isolated rabbit kidney cortex mitochondria. Toxicol In Vitro 25:1001-6
Wills, Lauren P; Schnellmann, Rick G (2010) Telomere shortening and regenerative capacity after acute kidney injury. J Am Soc Nephrol 21:202-4
Zhuang, Shougang; Lu, Bo; Daubert, Rebecca A et al. (2009) Suramin promotes recovery from renal ischemia/reperfusion injury in mice. Kidney Int 75:304-11
Zhuang, Shougang; Kinsey, Gilbert R; Yan, Yan et al. (2008) Extracellular signal-regulated kinase activation mediates mitochondrial dysfunction and necrosis induced by hydrogen peroxide in renal proximal tubular cells. J Pharmacol Exp Ther 325:732-40
Kinsey, Gilbert R; Blum, Jason L; Covington, Marisa D et al. (2008) Decreased iPLA2gamma expression induces lipid peroxidation and cell death and sensitizes cells to oxidant-induced apoptosis. J Lipid Res 49:1477-87
Kinsey, Gilbert R; McHowat, Jane; Patrick, Kennerly S et al. (2007) Role of Ca2+-independent phospholipase A2gamma in Ca2+-induced mitochondrial permeability transition. J Pharmacol Exp Ther 321:707-15

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