The long-term goal of this research is to elucidate the mechanisms of toxicant injury to renal proximal tubular cells (RPTC) that ultimately leads to acute renal failure. PLA2S are a rapidly growing family of enzymes that hydrolyze the sn-2 ester bond in phospholipids and play an important role in several signal transduction processes. Recent reports have shown that several different Ca2+-independent PLA2 (iPLA2) enzymes exist and that inhibition of iPLA2 decreases Fas-induced (i.e. ligand-mediated)-apoptosis. Data from our laboratory demonstrate that approximately 90 percent of PLA2 activity in rabbit proximal tubular cells (RPTC) is Ca2+-independent and located primarily in the membrane fraction. Furthermore, immunoblot analysis of RPTC identified a approximately 85 kDa band using an anti-iPLA2 antibody. The role of PLA2S in toxicant-induced cellular injury and apoptosis has received minimal attention. This proposal will test the central hypothesis that Cat+-independent membrane bound PLA2 (m-iPLA2) is a critical mediator of toxicant-induced apoptosis. Furthermore the RPTC m-iPLA2 will be identified.
Specific Aim 1 will determine the role of m-iPLA2 in t-butylhydroperoxide (TBHP) and cisplatin-induced apoptosis.
Specific Aim 2 will determine the site of action of m-iPLA2 in the signaling pathway of toxicant-induced RPTC apoptosis.
Specific Aim 3 will identify the iPLA2(S) in RPTC using a molecular biological approach. These data will increase our understanding of the signaling cascades that lead to cell injury and death and will aid in the development of future therapeutic agents that prevent or minimize acute renal failure.
| Sarang, Satinder S; Lukyanova, Svetlana M; Brown, Daniel D et al. (2008) Identification, coassembly, and activity of gamma-aminobutyric acid receptor subunits in renal proximal tubular cells. J Pharmacol Exp Ther 324:376-82 |
| Kinsey, Gilbert R; Cummings, Brian S; Beckett, Caroline S et al. (2005) Identification and distribution of endoplasmic reticulum iPLA2. Biochem Biophys Res Commun 327:287-93 |
| Cummings, Brian S; Gelasco, Andrew K; Kinsey, Gilbert R et al. (2004) Inactivation of endoplasmic reticulum bound Ca2+-independent phospholipase A2 in renal cells during oxidative stress. J Am Soc Nephrol 15:1441-51 |
| Cummings, Brian S; McHowat, Jane; Schnellmann, Rick G (2004) Role of an endoplasmic reticulum Ca2+-independent phospholipase A2 in cisplatin-induced renal cell apoptosis. J Pharmacol Exp Ther 308:921-8 |
| Cummings, Brian S; Kinsey, Gilbert R; Bolchoz, Laura J C et al. (2004) Identification of caspase-independent apoptosis in epithelial and cancer cells. J Pharmacol Exp Ther 310:126-34 |
| Cummings, Brian S; McHowat, Jane; Schnellmann, Rick G (2002) Role of an endoplasmic reticulum Ca(2+)-independent phospholipase A(2) in oxidant-induced renal cell death. Am J Physiol Renal Physiol 283:F492-8 |
| Cummings, Brian S; Schnellmann, Rick G (2002) Cisplatin-induced renal cell apoptosis: caspase 3-dependent and -independent pathways. J Pharmacol Exp Ther 302:8-17 |
