Complement C5b-9 induces receptor tyrosine kinase transactivation in glomerular epithelial cells

In the passive Heymann nephritis (PHN) model of membranous nephropathy, C5b -9 induces glomerular epithelial cell (GEC) injury and proteinuria, which i s partially mediated via production of eicosanoids, Using rat GEC in cultur e, we demonstrated that sublytic C5b-9 induced tyrosine phosphorylation of the epidermal growth factor receptor (EGF-R), Neu, fibroblast growth factor receptor-2, and hepatocyte growth factor receptor. In addition, C5b-9 stim ulated increases in tyrosine(204) phosphorylation of extracellular signal-r egulated kinase-2 (ERK2), as well as free [H-3]arachidonic acid (AA) and pr ostaglandin E-2 (PGE(2)). Phosphorylated EGF-R bound the adaptor protein, G rb2, and the EGF-R-selective tyrphostin, AG1478, blocked the C5b-9-induced ERK2 phosphorylation, [H-3]AA release, and PGE(2) production by 45 to 65%, supporting a functional role for EGF-R kinase in mediating the activation o f these pathways. Glomeruli belated from rats with PHN demonstrated increas es in ERK2 tyrosine(204) phosphorylation and PGE(2) production, as compared with glomeruli from control rats, and these increases were partially inhib ited with AG1478. Thus, C5b-9 induces transactivation of receptor tyrosine kinases, in association with ERK2 activation, AA release, and PGE(2) produc tion in cultured GEC and glomerulonephritis in vivo. Transactivated tyrosin e kinases may serve as scaffolds for assembly and/or activation of proteins , which then lead to activation of the ERK2 cascade and AA metabolism.