EPIDERMAL GROWTH-FACTOR AND PHORBOL-MYRISTATE ACETATE INCREASE EXPRESSION OF THE MESSENGERRNA FOR CYTOSOLIC PHOSPHOLIPASE-A(2) IN GLOMERULAR MESANGIAL CELLS

We have previously shown that phospholipase A2 (PLA2) activity is rapi dly activated by epidermal growth factor (EGF) and phorbol 12-myristat e 13-acetate (PMA) in renal mesangial cells and other cell systems in a manner that suggests a covalent modification of the PLA2 enzyme(s). This PLA2 activity is cytosolic (cPLA2) and is distinct from secretory forms of PLA2, which are also stimulated in mesangial cells in respon se to cytokines and other agonists. However, longer-term regulation of cPLA2 in renal cells may also occur at the level of gene expression. Cultured rat mesangial cells were used as a model system to test the e ffects of EGF and PMA on the regulation of cPLA2 gene expression. EGF and PMA both produced sustained increases in cPLA2 mRNA levels, with a parallel increase in enzyme activity over time. Inhibition of protein synthesis by cycloheximide increased basal cPLA2 mRNA accumulation in serum-starved mesangial cells, and the combination of EGF and cyclohe ximide resulted in super-induction of cPLA2 gene expression compared w ith EGF alone. Actinomycin D treatment entirely abrogated the effect o f EGF on cPLA2 mRNA accumulation. These findings suggest that regulati on of cPLA2 is achieved by factors controlling gene transcription and possibly mRNA stability, in addition to previously characterized post- translational modifications.