Abstract
Podocytes are the major site of vascular endothelial growth factor (VEGF) production in the kidney, and up-regulation of VEGF plays a critical role in the progression of diabetic nephropathy. Using a differentiated mouse podocyte cell line, we investigated the roles of protein kinase C (PKC) and extracellular signal-regulated kinase (ERK) on the expression of VEGF under high glucose conditions. High glucose induced up-regulation of VEGF mRNA and protein expression in podocytes via activation of PKC (PKC-alpha and -betaII isoforms) and ERK. High glucose stimulated [(3)H]leucine incorporation in the podocytes. High glucose and the PKC stimulator, phorbol 12-myristate 13-acetate (PMA) induced activator protein-1 (AP-1)-dependent transcriptional activity and expression of VEGF. In addition, these phenomena were blocked by specific inhibitors of PKC (GF10902X) and ERK kinase (PD98059). These observations suggested that high glucose-induced VEGF expression in podocytes was largely mediated through PKC and ERK pathways that may be involved in diabetic nephropathy.
(c)2002 Elsevier Science.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Differentiation
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Cell Line
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Cell Membrane / metabolism
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Cytosol / metabolism
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Dose-Response Relationship, Drug
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Endothelial Growth Factors / biosynthesis*
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Enzyme Inhibitors / pharmacology
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Flavonoids / pharmacology
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Glucose / metabolism
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Glucose / pharmacology*
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Kidney / cytology*
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Kidney / enzymology*
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Kidney / metabolism
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Leucine / metabolism
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Lymphokines / biosynthesis*
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Mice
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Mitogen-Activated Protein Kinases / metabolism*
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Mitogen-Activated Protein Kinases / physiology
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Protein Kinase C / metabolism*
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Protein Kinase C / physiology
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RNA, Messenger / metabolism
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Tetradecanoylphorbol Acetate / metabolism
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Time Factors
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Transcription Factor AP-1 / metabolism
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Transcription, Genetic
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
Substances
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Endothelial Growth Factors
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Enzyme Inhibitors
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Flavonoids
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Lymphokines
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RNA, Messenger
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Transcription Factor AP-1
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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Protein Kinase C
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Mitogen-Activated Protein Kinases
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Leucine
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Glucose
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Tetradecanoylphorbol Acetate
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one