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 is partially mediated via production of eicosanoids. Using rat GEC in culture, 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 stimulated increases in tyrosine(204) phosphorylation of extracellular signal-regulated kinase-2 (ERK2), as well as free [(3)H]arachidonic acid (AA) and prostaglandin E(2) (PGE(2)). Phosphorylated EGF-R bound the adaptor protein, Grb2, and the EGF-R-selective tyrphostin, AG1478, blocked the C5b-9-induced ERK2 phosphorylation, [(3)H]AA release, and PGE(2) production by 45 to 65%, supporting a functional role for EGF-R kinase in mediating the activation of these pathways. Glomeruli isolated from rats with PHN demonstrated increases in ERK2 tyrosine(204) phosphorylation and PGE(2) production, as compared with glomeruli from control rats, and these increases were partially inhibited with AG1478. Thus, C5b-9 induces transactivation of receptor tyrosine kinases, in association with ERK2 activation, AA release, and PGE(2) production in cultured GEC and glomerulonephritis in vivo. Transactivated tyrosine kinases may serve as scaffolds for assembly and/or activation of proteins, which then lead to activation of the ERK2 cascade and AA metabolism.
Cybulsky
A V
AV
Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada. cbulsky@pathology.lan.mcgill.ca
Takano
T
T
Papillon
J
J
McTavish
A J
AJ
D000818:Animals; D002478:Cells, Cultured; D015938:Complement Membrane Attack Complex / Q000235:genetics / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D005921:Glomerulonephritis / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007678:Kidney Glomerulus / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D015398:Signal Transduction / Q000235:genetics
D015938:Complement Membrane Attack Complex; D066246:ErbB Receptors