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Extracellular Signal-Regulated Kinase Mediates Stimulation of TGF-ß1 and Matrix by High Glucose in Mesangial Cells

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.

Correspondence to Dr. Fuad N. Ziyadeh, 700 Clinical Research Building, Renal-Electrolyte and Hypertension Division, University of Pennsylvania, 415 Curie Boulevard, Philadelphia, PA 19104-6144. Phone: 215-573-1837; Fax: 215-898-0189; E-mail: ziyadeh{at}mail.med.upenn.edu

Abstract. 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-ß (TGF-ß) 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-ß1 expression (total protein, mRNA levels, and promoter activity), [³H]-proline uptake, and 1(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 CL 100 prevented TGF-ß1 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-ß1 and contributes to the increased extracellular matrix expression.

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