Suppression of NF-κB and AP-1 activation by glucocorticoids in experimental glomerulonephritis in rats: molecular mechanisms of anti-nephritic action

Abstract Transcription factors nuclear factor- κ B (NF- κ B) and activator protein-1 (AP-1) play an important role in the induction of pro-inflammatory factors such as cytokines and cell adhesion molecules, which could be involved in the pathogenesis of glomerulonephritis. We have recently reported the pathogenic significance of NF- κ B activation in experimental glomerulonephritis in rats. In this study, we investigated 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- κ B. Activation of both NF- κ B and AP-1 preceded proteinuria, an important pathophysiological parameter for glomerulonephritis. Treatment with prednisolone, a glucocorticoid hormone, prevented activation of both NF- κ B and AP-1 in glomeruli and subsequent mRNA expression of NF- κ B- and AP-1-regulated genes. Prednisolone was also effective therapeutically and reduced DNA-binding activities of NF- κ B and AP-1 which are already activated in nephritic glomeruli. These results suggest that activated NF- κ B and AP-1 may play an important pathogenic role in glomerulonephritis and the anti-nephritic action of glucocorticoids may be mediated through the suppression of these transcription factors.