Complement C5b-9 induces cyclooxygenase-2 gene transcription in glomerularepithelial cells

In rat membranous nephropathy, complement C5b-9 induces glomerular epitheli al cell (GEC) injury and proteinuria, which is partially mediated by eicosa noids. Rat GEC in culture express cyclooxygenase (COX)-1 constitutively, wh ereas COX-2 expression is induced by C5b-9. Both isoforms contribute to com plement-induced prostaglandin generation. The present study addresses mecha nisms of complement-induced COX-2 expression in GEC. Downregulation of prot ein kinase C (PKC) blunted complement-induced upregulation of COX-2 mRNA. C omplement and phorbol 12-myristate 13-acetate (PMA) both stimulated COX-2 p romoter activity. C5b-9 activated c-Jun NH2-terminal kinase (JNK), and inhi bition of JNK activity by transfection of a kinase-inactive JNK1 partially inhibited complement-induced (but not PMA-induced) COX-2 promoter activatio n. Conversely, a constitutively active mitogen-activated protein or extrace llular signal-regulated kinase kinase kinase (MEKK)-1, a kinase upstream of JNK, increased COX-2 promoter activity. MEKK-induced COX-2 promoter activa tion was not affected by downregulation of PKC and was augmented by PMA. Th us, in GEC, PKC and JNK pathways contribute independently to complement-ind uced COX-2 expression. Nuclear factor-kappaB was also activated by compleme nt in GEC but did not contribute to complement-induced COX-2 upregulation.