High glucose induced VEGF expression via PKC and ERK in glomerular podocytes.
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.
Hoshi
Sachi
S
Department of Pathology, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
Nomoto
Ken-ichi
K
Kuromitsu
Junro
J
Tomari
Shinsuke
S
Nagata
Michio
M
D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D016228:Endothelial Growth Factors / Q000096:biosynthesis*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology*; D007668:Kidney / Q000166:cytology* / Q000201:enzymology* / Q000378:metabolism; D007930:Leucine / Q000378:metabolism; D008222:Lymphokines / Q000096:biosynthesis*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism* / Q000502:physiology; D011493:Protein Kinase C / Q000378:metabolism* / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000378:metabolism; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D005419:Flavonoids; D008222:Lymphokines; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D007930:Leucine; D005947:Glucose; D013755:Tetradecanoylphorbol Acetate; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one