Effects of prednisolone on glomerular signal transduction cascades in experimental glomerulonephritis.
In vitro data support that activator protein-1 (AP-1) and nuclear factor-kappaB (NF-kappaB) regulate the gene expression of numerous growth factors and cytokines involved in the development of glomerulonephritis (GN). However, the in vivo activation and role of these transcription factors are poorly understood. This study examines whether these transcription factors are activated in antithymocyte serum (ATS)-induced GN in vivo and whether prednisolone suppresses activation of them. As assessed by gel mobility shift assay, glomerular DNA binding activity of AP-1 containing both c-Jun and c-Fos and NF-kappaB composed of P-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 (ERK) and c-jun NH2-terminal kinases (JNK), which are mitogen-activated protein kinases (MAPK) known to activate AP-1 and NF-kappaB in vitro, was significantly increased after ATS injection, preceding the increase in AP-1 activity. Prednisolone treatment significantly prevented the increase in urinary protein and albumin excretion and glomerular cell proliferation in ATS-induced GN, indicating the beneficial effects of prednisolone on this GN. Prednisolone significantly suppressed the increased glomerular ERK and JNK activities and AP-1 binding activity, but not glomerular NF-kappa binding activity. This study provides the first evidence of the marked increase in glomerular MAPK activities, and AP-1 and NF-kappa binding activities in ATS-induced GN. The beneficial effect of prednisolone on this GN may be partially mediated by the suppression of MAPK, followed by the suppression of AP-1.
Department of Pharmacology, Osaka City University Medical School, Japan.
M
M
Seto
S
S
Kim
H
H
Yoshifusa
Y
Y
Nakamura
T
T
Masuda
A
A
Hamaguchi
S
S
Yamanaka
H
H
Iwao
D000818:Animals; D000961:Antilymphocyte Serum / Q000008:administration & dosage; D001483:Base Sequence; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D005260:Female; D005921:Glomerulonephritis / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology*; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011239:Prednisolone / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism
D000961:Antilymphocyte Serum; D017931:DNA Primers; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D004247:DNA; D011239:Prednisolone; D017871:Calcium-Calmodulin-Dependent Protein Kinases