TY - JOUR
T1 - Extracellular signal-regulated kinase mediates stimulation of TGF-β1 and matrix by high glucose in mesangial cells
AU - Isono, Motohide
AU - Iglesias-De La Cruz, M. Carmen
AU - Chen, Sheldon
AU - Hong, Soon Won
AU - Ziyadeh, Fuad N.
PY - 2000
Y1 - 2000
N2 - High ambient glucose exerts its injurious effects on renal cells through nonenzymatic and enzymatic pathways, including altered signal transduction and upregulation of the transforming growth factor-β (TGF-β) system. Extracellular signal-regulated kinase (ERK), a member of the mitogen-activated protein kinase (MAPK) cascade, is activated in mesangial cells cultured in high glucose and in glomeruli of diabetic rats. However, the biologic consequences of ERK activation in the kidney have not been investigated. To clarify the role of ERK activation, mouse mesangial cells were exposed to normal (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 increases in ERK activity, TGF-β1 expression (total protein, mRNA levels, and promoter activity), [3H]-proline uptake, and α1(I) collagen and fibronectin mRNA levels. Treatment with PD98059 (up to 25 μM) significantly inhibited these parameters. In contrast, 25 μM PD98059 had no significant effect on any of the parameters measured in cells that were exposed to normal glucose. Overexpression of MAPK phosphatase CL100 prevented TGF-β1 promoter activation by high glucose, confirming the involvement of the MEK-ERK pathway in response to high glucose. The conclusion is that activation of ERK in mesangial cells is responsible for high-glucose-induced stimulation of TGF-β1 and contributes to the increased extracellular matrix expression.
AB - High ambient glucose exerts its injurious effects on renal cells through nonenzymatic and enzymatic pathways, including altered signal transduction and upregulation of the transforming growth factor-β (TGF-β) system. Extracellular signal-regulated kinase (ERK), a member of the mitogen-activated protein kinase (MAPK) cascade, is activated in mesangial cells cultured in high glucose and in glomeruli of diabetic rats. However, the biologic consequences of ERK activation in the kidney have not been investigated. To clarify the role of ERK activation, mouse mesangial cells were exposed to normal (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 increases in ERK activity, TGF-β1 expression (total protein, mRNA levels, and promoter activity), [3H]-proline uptake, and α1(I) collagen and fibronectin mRNA levels. Treatment with PD98059 (up to 25 μM) significantly inhibited these parameters. In contrast, 25 μM PD98059 had no significant effect on any of the parameters measured in cells that were exposed to normal glucose. Overexpression of MAPK phosphatase CL100 prevented TGF-β1 promoter activation by high glucose, confirming the involvement of the MEK-ERK pathway in response to high glucose. The conclusion is that activation of ERK in mesangial cells is responsible for high-glucose-induced stimulation of TGF-β1 and contributes to the increased extracellular matrix expression.
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M3 - Article
C2 - 11095645
AN - SCOPUS:0033662740
SN - 1046-6673
VL - 11
SP - 2222
EP - 2230
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
IS - 12
ER -