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Articles in PresS, published online ahead of print April 16, 2002
Am J Physiol Renal Physiol, 10.1152/ajprenal.00022.2002
Submitted on January 16, 2002
Accepted on April 14, 2002
1 Department of Pharmaceutical Sciences, Medical University of South Carolina, Charleston, SC, USA
2 Department of Pathology, Saint Louis University, St. Louis, MO, USA
* To whom correspondence should be addressed. E-mail: schnell{at}musc.edu.
Phospholipases A2 (PLA2) hydrolyze the sn-2 ester bond in phospholipids releasing a fatty acid and a lysophospholipid. Recently, a novel 85 kDa membrane bound Ca2+-independent PLA2 (iPLA2) has been identified in insect and bacterial cells transfected with candidate PLA2 sequences. However, little data exist demonstrating a membrane bound-iPLA2 in mammalian cells, its sub-cellular localization or its physiological role. Herein, we demonstrate the expression of an 85 kDa endoplasmic reticulum Ca2+-independent PLA2 (ER-iPLA2) in rabbit renal proximal tubule cells (RPTC) that is plasmalogen selective and is inhibited by the specfic Ca2+-independent PLA2 inhibitor bromoenol lactone (BEL). RPTC exposed to tert-butylhydroperoxide (TBHP) for 24 hr exhibited 20% oncosis compared to 2% in controls. Inhibition of ER-iPLA2 with BEL prior to TBHP exposure resulted in 50% oncosis. To determine if this effect was common to oxidants, we tested the ability of BEL to potentiate oncosis induced cumene hydroperoxide, menadione, duraquinone, cisplatin and the non-oxidant antimycin A. All oxidants tested increased oncosis after 24 hr and prior inhibition of ER-iPLA2 potentiated oncosis at least two-fold. In contrast, inhibition of ER-iPLA2 did not alter antimycin A-induced oncosis. Lipid peroxidation increased 1.4 to 5.2-fold in RPTC treated with BEL prior to oxidant exposure while no change was seen in antimycin A treated RPTC. These results are the first to demonstrate the expression and sub-cellular localization of an ER-iPLA2. These results also suggest that ER-iPLA2 functions to protect against oxidant-induced lipid peroxidation and oncosis.
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