Role of an endoplasmic reticulum Ca2+-independent phospholipase A2 in cisplatin-induced renal cell apoptosis.
It has been demonstrated recently that rabbit renal proximal tubule cells (RPTC) express a novel Ca(2+)-independent phospholipase A(2) (iPLA(2)) whose activity localizes to the endoplasmic reticulum (ER-iPLA(2)) and is similar to group VIB PLA(2). In this study, the expression of group VIB PLA(2) was examined and the role of ER-iPLA(2) 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-iPLA(2) with bromoenol lactone (5 microM) 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-iPLA(2) 2-fold and increased cisplatin-induced RPTC apoptosis. These studies demonstrate that group VIB PLA(2) is expressed in RPTC and suggest that RPTC ER-iPLA(2) is the rabbit homolog of group VIB PLA(2). These data also demonstrate that ER-iPLA(2) acts downstream of p53 and upstream of caspase 3 to mediate cisplatin-induced RPTC apoptosis. Finally, ER-iPLA(2) seems to be regulated by protein kinase C.
Cummings
Brian S
BS
Department of Pharmaceutical Sciences, Medical University of South Carolina, Charleston, SC 29425, USA.
McHowat
Jane
J
Schnellmann
Rick G
RG
D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology*; D002118:Calcium / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D002843:Chromatin / Q000187:drug effects / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology; D004247:DNA / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000201:enzymology*; D005260:Female; D007668:Kidney / Q000166:cytology*; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000502:physiology*; D054467:Phospholipases A2; D011817:Rabbits; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D017304:Annexin A5; D002843:Chromatin; D016159:Tumor Suppressor Protein p53; D004247:DNA; D010741:Phospholipases A; D054467:Phospholipases A2; D020169:Caspases; D013755:Tetradecanoylphorbol Acetate; D002945:Cisplatin; D002118:Calcium