title: Suppression of NF-kappa B and AP-1 activation by glucocorticoids in experimental glomerulonephritis in rats: molecular mechanisms of anti-nephritic action.
abstract: Transcription factors nuclear factor-kappa B (NF-kappa 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-kappa 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-kappa B. Activation of both NF-kappa B and AP-1 preceded proteinuria, an important pathophysiological 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 AP-1-regulated genes. Prednisolone was also effective therapeutically and reduced DNA-binding activities of NF-kappa B and AP-1 which are already activated in nephritic glomeruli. These results suggest that activated NF-kappa 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.
authors.affiliation: Lead Generation Research Laboratory, Tanabe Seiyaku Co., Ltd., Osaka, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Sakurai
authors.forename: N
authors.initials: N
authors.lastname: Shigemori
authors.forename: Y
authors.initials: Y
authors.lastname: Hisada
authors.forename: T
authors.initials: T
authors.lastname: Ishizuka
authors.forename: K
authors.initials: K
authors.lastname: Kawashima
authors.forename: T
authors.initials: T
authors.lastname: Sugita
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D002467:Cell Nucleus / Q000378:metabolism; D018932:Chemokine CCL2 / Q000235:genetics; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D005921:Glomerulonephritis / Q000276:immunology / Q000378:metabolism*; D005938:Glucocorticoids / Q000494:pharmacology*; D007249:Inflammation / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D007375:Interleukin-1 / Q000235:genetics; D007678:Kidney Glomerulus / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D011239:Prednisolone / Q000494:pharmacology; D011507:Proteinuria / Q000378:metabolism; D051381:Rats; D011921:Rats, Inbred WKY; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics
chemical_list: D018932:Chemokine CCL2; D004268:DNA-Binding Proteins; D005938:Glucocorticoids; D007375:Interleukin-1; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D016212:Transforming Growth Factor beta; D018799:Intercellular Adhesion Molecule-1; D004247:DNA; D011239:Prednisolone