Extracellular signal-regulated kinase mediates stimulation of TGF-beta1 and matrix by high glucose in mesangial cells.
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-beta (TGF-beta) 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-beta1 expression (total protein, mRNA levels, and promoter activity), [(3)H]-proline uptake, and alpha1(I) collagen and fibronectin mRNA levels. Treatment with PD98059 (up to 25 microM) significantly inhibited these parameters. In contrast, 25 microM PD98059 had no significant effect on any of the parameters measured in cells that were exposed to normal glucose. Overexpression of MAPK phosphatase CL 100 prevented TGF-beta1 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-beta1 and contributes to the increased extracellular matrix expression.
Isono
Motohide
M
Renal-Electrolyte and Hypertension Division of the Department of Medicine and the Penn Center for the Molecular Studies of Kidney Diseases, University of Pennsylvania, Philadelphia, Pennsylvania.
Cruz
M Carmen Iglesias-DE LA
MCI
Renal-Electrolyte and Hypertension Division of the Department of Medicine and the Penn Center for the Molecular Studies of Kidney Diseases, University of Pennsylvania, Philadelphia, Pennsylvania.
Chen
Sheldon
S
Renal-Electrolyte and Hypertension Division of the Department of Medicine and the Penn Center for the Molecular Studies of Kidney Diseases, University of Pennsylvania, Philadelphia, Pennsylvania.
Hong
Soon Won
SW
Renal-Electrolyte and Hypertension Division of the Department of Medicine and the Penn Center for the Molecular Studies of Kidney Diseases, University of Pennsylvania, Philadelphia, Pennsylvania.
Ziyadeh
Fuad N
FN
Renal-Electrolyte and Hypertension Division of the Department of Medicine and the Penn Center for the Molecular Studies of Kidney Diseases, University of Pennsylvania, Philadelphia, Pennsylvania.
D000818:Animals; D018797:Cell Cycle Proteins; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D054638:Dual Specificity Phosphatase 1; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D005947:Glucose / Q000008:administration & dosage / Q000494:pharmacology*; D017874:Immediate-Early Proteins / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*; D010749:Phosphoprotein Phosphatases; D011401:Promoter Regions, Genetic / Q000502:physiology; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1
D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D017874:Immediate-Early Proteins; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D020928:Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse; D017027:Protein Tyrosine Phosphatases; D005947:Glucose; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one