ERK contributes to the effects of Smad signaling on oxidized LDL‐induced PAI‐1 experssion in human mesangial cells

• Published in: The FASEB journal 2007, Vol.21 (6), p.A1132-A1132
• Main Authors: Hong, Hye kyoung, Song, Chi young, Kim, Bong cho, Kang, Gyeung hoon, Lee, Hyun soon
• Format: Article
• Language: English
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fasebj.21.6.A1132-b

Hypercholesterolemia and lipoprotein abnormalities are risk factors for the progression of glomerular injury to glomerulosclerosis. 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. Thus, in patients with chronic renal disease and persistent hypercholesterolemia, ERK activation by Ox‐LDL might contribute to mesangial ECM accumulation and subsequently renal fibrosis due to interaction between Ox‐LDL and the Smad signaling pathway.