Homocysteine stimulates monocyte chemoattractant protein-1 expression in mesangial cells via NF-kappaB activation.
Hyperhomocysteinemia is regarded as an independent risk factor for cardiovascular disorders. Although renal dysfunction or failure is one of the important factors causing hyperhomocysteinemia, the role of homocysteine (Hcy) in the development of glomerulosclerosis is largely unknown. One of the key events in the pathogenesis of glomerulosclerosis is the infiltration of circulating monocytes into affected glomeruli. The objective of the present study was to investigate the effect of Hcy on the expression of monocyte chemoattractant protein-1 (MCP-1) in kidney mesangial cells and the mechanisms involved. Levels of MCP-1 and mRNA were significantly elevated in Hcy-treated rat mesangial cells. This increase was associated with activation of NF-kappaB as a result of increased phosphorylation of the inhibitor protein IkappaBalpha. Monocyte chemotactic activity in these cells was also enhanced. In addition, there was a significant elevation of superoxide anion produced by Hcy-treated cells, which preceded the increased phosphorylation of IkappaBalpha. Addition of superoxide dismutase or NF-kappaB inhibitors to the culture medium abolished Hcy-induced NF-kappaB activation and MCP-1 expression. Taken together, these results indicate that Hcy induced MCP-1 expression in mesangial cells. Such a process was mediated by oxidative stress and NF-kappaB activation. This may further aggravate renal function in patients with hyperhomocysteinemia.
Cheung
Giselle T Y
GT
Department of Animal Science, University of Manitoba, Integrative Biology Laboratory, St. Boniface Hospital Research Centre, Winnipeg, MB R2H2A6, Canada.
Siow
Yaw L
YL
O
Karmin
K
D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D024202:Electrophoretic Mobility Shift Assay; D016166:Free Radical Scavengers / Q000494:pharmacology; D006710:Homocysteine / Q000494:pharmacology*; D008297:Male; D050527:Mesangial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008954:Models, Biological; D009000:Monocytes / Q000187:drug effects / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D011092:Polyethylene Glycols / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013482:Superoxide Dismutase / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism
D018932:Chemokine CCL2; D016166:Free Radical Scavengers; D016328:NF-kappa B; D009687:Nuclear Proteins; D012333:RNA, Messenger; D006710:Homocysteine; D013481:Superoxides; D011092:Polyethylene Glycols; D013482:Superoxide Dismutase; C063471:polyethylene glycol-superoxide dismutase