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Am J Physiol Renal Physiol 294: F469-F479, 2008. First published January 2, 2008; doi:10.1152/ajprenal.00372.2007
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Role of calcium-independent phospholipase A2 in complement-mediated glomerular epithelial cell injury

Daniel Cohen,2 Joan Papillon,1 Lamine Aoudjit,1 Hongping Li,1 Andrey V. Cybulsky,1,2,* and Tomoko Takano1,2,*

Departments of 1Medicine and 2Physiology, McGill University, Montreal, Quebec, Canada

Submitted 7 August 2007 ; accepted in final form 28 December 2007

In experimental membranous nephropathy, complement C5b-9-induced glomerular epithelial cell (GEC) injury leads to morphological changes in GEC and proteinuria, in association with phospholipase A2 (PLA2) activation. The present study addresses the role of calcium-independent PLA2 (iPLA2) in GEC injury. iPLA2β short and iPLA2{gamma} were expressed in cultured rat GEC and normal rat glomeruli. To determine whether iPLA2 is involved in complement-mediated arachidonic acid (AA) release, GEC were stably transfected with iPLA2{gamma} or iPLA2β cDNAs (GEC-iPLA2{gamma}; GEC-iPLA2β). Compared with control cells (GEC-Neo), GEC-iPLA2{gamma} and GEC-iPLA2β demonstrated greater expression of iPLA2 proteins and activities. Complement-mediated release of [3H]AA was augmented significantly in GEC-iPLA2{gamma} compared with GEC-Neo, and the augmented [3H]AA release was inhibited by the iPLA2-directed inhibitor bromoenol lactone (BEL). For comparison, overexpression of iPLA2{gamma} also amplified [3H]AA release after incubation of GEC with H2O2, or chemical anoxia followed by reexposure to glucose (in vitro ischemia-reperfusion injury). In parallel with release of [3H]AA, complement-mediated production of prostaglandin E2 was amplified in GEC-iPLA2{gamma}. Complement-mediated cytotoxicity was attenuated significantly in GEC-iPLA2{gamma} compared with GEC-Neo, and the cytoprotective effect of iPLA2{gamma} was reversed by BEL, and in part by indomethacin. Overexpression of iPLA2β did not amplify complement-dependent [3H]AA release, but nonetheless attenuated complement-mediated cytotoxicity. Thus iPLA2{gamma} may be involved in complement-mediated release of AA. Expression of iPLA2{gamma} or iPLA2β induces cytoprotection against complement-dependent GEC injury. Modulation of iPLA2 activity may prove to be a novel approach to reducing GEC injury.

iPLA2β; iPLA2{gamma}; cytoprotection


Address for reprint requests and other correspondence: T. Takano, Div. of Nephrology, McGill Univ., 3775 Univ. St., Rm. 236, Montreal, Quebec, Canada H3A2B4 (e-mail: tomoko.takano{at}mcgill.ca)






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