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TOXICOLOGY
Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, Georgia (B.S.C.); Department of Pathology, Saint Louis University, St. Louis, Missouri (J.M.); and Department of Pharmaceutical Sciences, Medical University of South Carolina, Charleston, South Carolina (R.G.S.)
It has been demonstrated recently that rabbit renal proximal tubule cells (RPTC) express a novel Ca2+-independent phospholipase A2 (iPLA2) whose activity localizes to the endoplasmic reticulum (ER-iPLA2) and is similar to group VIB PLA2. In this study, the expression of group VIB PLA2 was examined and the role of ER-iPLA2 in cisplatin-induced apoptosis was determined. Cisplatin induced both time- and concentration-dependent RPTC apoptosis as determined by p53 nuclear localization, annexin V staining, caspase 3 activity, and chromatin condensation. Inhibition of ER-iPLA2 with bromoenol lactone (5 µM) reduced cisplatin-induced annexin V binding 40%, chromatin condensation 55%, and caspase 3 activity 42%, but had no effect on p53 nuclear localization. Treatment of RPTC with the protein kinase C stimulator phorbol 12-myristate 13-acetate increased the activity of ER-iPLA2 2-fold and increased cisplatin-induced RPTC apoptosis. These studies demonstrate that group VIB PLA2 is expressed in RPTC and suggest that RPTC ER-iPLA2 is the rabbit homolog of group VIB PLA2. These data also demonstrate that ER-iPLA2 acts downstream of p53 and upstream of caspase 3 to mediate cisplatin-induced RPTC apoptosis. Finally, ER-iPLA2 seems to be regulated by protein kinase C.
Address correspondence to: Dr. Rick G. Schnellmann, Department of Pharmaceutical Sciences, Medical University of South Carolina, Charleston, SC 29425. E-mail: schnell{at}musc.edu
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