EFFECTS OF PREDNISOLONE ON GLOMERULAR SIGNAL-TRANSDUCTION CASCADES INEXPERIMENTAL GLOMERULONEPHRITIS

In vitro data support that activator protein-1 (AP-1) and nuclear fact or-kappa B (NF-kappa B) regulate the gene expression of numerous growt h factors and cytokines involved in the development of glomerulonephri tis (GN). However, the in vivo activation and role of these transcript ion factors are poorly understood, This study examines whether these t ranscription factors are activated in antithymocyte serum (ATS)-induce d GN in vivo and whether prednisolone suppresses activation of them. A s assessed by gel mobility shift assay, glomerular DNA binding activit y of AP-1 containing both c-Jun and c-Fos and NF-kappa B composed of F -50 and P-65 subunits was significantly increased after ATS injection. Furthermore, as estimated by in-gel kinase assay, glomerular activity of extracellular signal-regulated kinases (ERE;) and c-jun NH2-termin al kinases (JNK), which are mitogen-activated protein kinases (MAPK) k nown to activate AP-1 and NF-kappa B in vitro, was significantly incre ased after ATS injection, preceding the increase in AP-1 activity. Pre dnisolone treatment significantly prevented the increase in urinary pr otein and albumin excretion and glomerular cell proliferation in ATS-i nduced GN, indicating the beneficial effects of prednisolone on this G N. Prednisolone significantly suppressed the increased glomerular ERR and JNK activities and AP-1 binding activity, but not glomerular NF-ka ppa binding activity. This study provides the first evidence of the ma rked increase in glomerular MAPK activities, and AP-1 and NF-kappa bin ding activities in ATS-induced GN. The beneficial effect of prednisolo ne on this GN may be partially mediated by the suppression of MAPK, fo llowed by the suppression of AP-1.