SUPPRESSION OF NF-KAPPA-B AND AP-1 ACTIVATION BY GLUCOCORTICOIDS IN EXPERIMENTAL GLOMERULONEPHRITIS IN RATS - MOLECULAR MECHANISMS OF ANTI-NEPHRITIC ACTION

Transcription factors nuclear factor-kappa B (NF-kappa B) and activato r protein-1 (AP-1) play an important role in the induction of pro-infl ammatory factors such as cytokines and cell adhesion molecules, which could be involved in the pathogenesis of glomerulonephritis. We have r ecently reported the pathogenic significance of NF-kappa B activation in experimental glomerulonephritis in rats. In this study, we investig ated the pathogenic relevance of AP-1 activation in nephrotoxic serum (NTS)-induced glomerulonephritis. Increased AP-1 DNA-binding activity was detected in nephritic glomeruli by a gel shift assay. The kinetics of AP-1 activation was similar to that of NF-kappa B. Activation of b oth NF-kappa B and AP-1 preceded proteinuria, an important pathophysio logical parameter for glomerulonephritis. Treatment with prednisolone, a glucocorticoid hormone, prevented activation of both NF-kappa B and AP-1 in glomeruli and subsequent mRNA expression of NF-kappa B- and A P-1-regulated genes. Prednisolone was also effective therapeutically a nd reduced DNA-binding activities of NF-kappa B and AP-1 which are alr eady activated in nephritic glomeruli. These results suggest that acti vated NF-kappa B and AP-1 may play an important pathogenic role in glo merulonephritis and the anti-nephritic action of glucocorticoids may b e mediated through the suppression of these transcription factors. (C) 1997 Elsevier Science B.V.