ERK contributes to the effects of Smad signaling on oxidized LDL-induced PAI-1 expression in human mesangial cells.
Oxidized low-density lipoprotein (Ox-LDL) stimulates plasminogen activator inhibitor-1 (PAI-1) expression in human mesangial cells mediated by transforming growth factor-beta (TGF-beta)/Smad signaling pathway. TGF-beta activates extracellular signal-regulated kinase (ERK) in mesangial cells, and ERK is involved in activation of Smad2/3. This study examines whether an interaction exists between Ox-LDL-induced TGF-beta/Smad signaling pathways and ERK activation leading to PAI-1 transcription in human mesangial cells. Ox-LDL (50 microg/mL) induced an acute increase in ERK activity within 15 min, which decreased to control value at 2 h. Incubation with anti-TGF-beta or SB-431542, an inhibitor of the TGF-beta type I receptor, along with Ox-LDL, inhibited the expected increase in ERK phosphorylation. Treatment with PD98059 or UO126, mitogen-activated ERK-activating kinase 1/2 inhibitors, significantly inhibited the Ox-LDL-induced increase in PAI-1 mRNA and nuclear Smad3 expression, DNA/protein complex formation, and PAI-1 promoter activity. These results suggest that phosphorylation of ERK is induced by Ox-LDL through the induction of the TGF-beta signaling pathway and that activated ERK, in turn, participates in the Ox-LDL-induced Smad3 activation and subsequent PAI-1 gene expression in mesangial cells.
Hong
Hye Kyoung
HK
Department of Pathology, Seoul National University College of Medicine, Chongno-gu, Seoul, Korea.
Song
Chi Young
CY
Kim
Bong Cho
BC
Lee
Hyun Soon
HS
D019138:Antibodies, Blocking / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D002478:Cells, Cultured; D004149:Dioxoles / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D005920:Glomerular Mesangium / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism*; D051900:Smad3 Protein / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000276:immunology
C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D019138:Antibodies, Blocking; D001549:Benzamides; D002070:Butadienes; D004149:Dioxoles; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D005419:Flavonoids; D008077:Lipoproteins, LDL; D009570:Nitriles; D017395:Plasminogen Activator Inhibitor 1; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; C113580:U 0126; C099252:oxidized low density lipoprotein; D048049:Extracellular Signal-Regulated MAP Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one