Extracellular signal-regulated kinase mediates stimulation of TGF-beta 1 and matrix by high glucose in mesangial cells

Citation
M. Isono et al., Extracellular signal-regulated kinase mediates stimulation of TGF-beta 1 and matrix by high glucose in mesangial cells, J AM S NEPH, 11(12), 2000, pp. 2222-2230
Citations number
50
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Urology & Nephrology","da verificare
Journal title
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
ISSN journal
1046-6673 → ACNP
Volume
11
Issue
12
Year of publication
2000
Pages
2222 - 2230
Database
ISI
SICI code
1046-6673(200012)11:12<2222:ESKMSO>2.0.ZU;2-5
Abstract
High ambient glucose exerts its injurious effects on renal cells through no nenzymatic and enzymatic pathways, including altered signal transduction an d upregulation of the transforming growth factor-beta (TGF-beta) system. Ex tracellular signal-regulated kinase (ERK), a member of the mitogen-activate d protein kinase (MAPK) cascade, is activated in mesangial cells cultured i n high glucose and in glomeruli of diabetic rats. However, the biologic con sequences of ERK activation in the kidney have not been investigated. To cl arify the role of ERK activation, mouse mesangial cells were exposed to nor mal (5.5 mM) or high (25 mM) glucose with or without addition of PD98059, a specific inhibitor of MAPK/ERK kinase (MEK), an upstream kinase activator of ERK. Cells that were exposed to high glucose exhibited significant incre ases in ERK activity, TGF-beta1 expression (total protein, mRNA levels, and promoter activity), [H-3]-proline uptake, and alpha1(I) collagen and fibro nectin mRNA levels. Treatment with PD98059 (up to 25 muM) significantly inh ibited these parameters. In contrast, 25 muM PD98059 had no significant eff ect on any of the parameters measured in cells that were exposed to normal glucose. Overexpression of MAPK phosphatase CL100 prevented TGF-beta1 promo ter activation by high glucose, confirming the involvement of the MEK-ERK p athway in response to high glucose. The conclusion is that activation of ER K in mesangial cells is responsible for high-glucose-induced stimulation of TGF-beta1 and contributes to the increased extracellular matrix expression .