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Department of Medicine, McGill University Health Centre, McGill University, Montreal, Quebec, Canada H3A 1A1
Submitted 22 July 2003 ; accepted in final form 21 November 2003
Cytosolic PLA2-
(cPLA2) and metabolites of arachidonic acid (AA) are key mediators of complement-dependent glomerular epithelial cell (GEC) injury. Assembly of C5b-9 increases cytosolic Ca2+ concentration and results in transactivation of receptor tyrosine kinases and activation of PLC-
1 and the 1,2-diacylglycerol (DAG)-PKC pathway. Ca2+ and PKC are essential for membrane association and increased catalytic activity of cPLA2. This study addresses the role of the actin cytoskeleton in cPLA2 activation. Depolymerization of F-actin by cytochalasin D or latrunculin B reduced complement-dependent [3H]AA release, as well as the complement-induced increase in cPLA2 activity. These effects were due to inhibition of [3H]DAG production and PKC activation, implying interference with PLC. Complement-dependent [3H]AA release was also reduced by jasplakinolide, a compound that stabilizes F-actin and organizes actin filaments at the cell periphery, and calyculin A, which induces condensation of actin filaments at the plasma membrane. The latter drugs did not affect [3H]DAG production, suggesting their inhibitory actions were downstream of PKC. Neither cytochalasin D, latrunculin B, nor calyculin A affected association of cPLA2 with microsomal membranes, and cytochalasin D and latrunculin B did not alter the localization of the endoplasmic reticulum. Stable transfection of constitutively active RhoA induced formation of stress fibers, stabilized F-actin, and attenuated the complement-induced increase in [3H]AA. Thus in GEC, cPLA2 activation is dependent, in part, on actin remodeling. By regulating complement-mediated activation of cPLA2, the actin cytoskeleton may contribute to the pathophysiology of GEC injury.
inflammation; lipid mediators; protein kinases; signal transduction
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