Abstract
Increased expression of endothelin-1 (ET-1) is associated with diabetic retinopathy and vasculopathy, although the molecular explanation has not been defined. The effects of high glucose and protein kinase C (PKC) activation on platelet-derived growth factor (PDGF)-BB and of ET-1 expression in the retina of streptozotocin (STZ)-induced diabetic rats and bovine retinal pericytes (BRPC) were examined. In 4-week diabetic rats, PDGF-B and prepro-ET-1 (ppET-1) mRNA levels increased significantly by 2.8- and 1.9-fold, respectively, as quantified by RT-PCR. Treatment with PKC-beta isoform-specific inhibitor (LY333531) or insulin normalized retinal ET-1 and PDGF-B expression. In BRPC, high glucose levels increased ppET-1 and PDGF-B mRNA expression by 1.7- and 1.9-fold, respectively. The addition of PDGF-BB but not PDGF-AA increased expression of ppET-1 and vascular endothelial growth factor mRNA by 1.6- and 2.1-fold, respectively, with both inhibited by AG1296, a selective PDGF receptor kinase inhibitor. A general PKC inhibitor, GF109203X, suppressed PDGF-BB's induction of ET-1 mRNA. Thus, increased ET-1 expression in diabetic retina could be due to increased expression of PDGF-BB, mediated via PDGF-beta receptors in part by PKC activation. The novel demonstration of elevated expression of PDGF-B and its induction by PKC activation identifies a potential new molecular step in the pathogenesis of diabetic retinopathy.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Becaplermin
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Capillaries / chemistry
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Cells, Cultured
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Diabetes Mellitus, Experimental / metabolism*
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Diabetic Retinopathy / etiology
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Endothelial Growth Factors / genetics
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Endothelin Receptor Antagonists
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Endothelin-1 / genetics*
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Enzyme Activation
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Enzyme Inhibitors / pharmacology
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Gene Expression / drug effects
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Indoles / pharmacology
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Insulin / therapeutic use
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Intercellular Signaling Peptides and Proteins / genetics
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Lymphokines / genetics
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Male
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Maleimides / pharmacology
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Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
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Platelet-Derived Growth Factor / genetics*
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Platelet-Derived Growth Factor / pharmacology
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Protein Kinase C / antagonists & inhibitors
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Protein Kinase C / physiology*
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Protein Kinase C beta
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Proto-Oncogene Proteins c-sis / genetics
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RNA, Messenger / analysis
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Rats
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Rats, Sprague-Dawley
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Receptor, Endothelin A
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Retina / chemistry*
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Retinal Vessels / chemistry*
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Reverse Transcriptase Polymerase Chain Reaction
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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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Endothelin Receptor Antagonists
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Endothelin-1
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Enzyme Inhibitors
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Indoles
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Insulin
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Intercellular Signaling Peptides and Proteins
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Lymphokines
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Maleimides
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Platelet-Derived Growth Factor
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Proto-Oncogene Proteins c-sis
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RNA, Messenger
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Receptor, Endothelin A
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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platelet-derived growth factor A
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Becaplermin
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ruboxistaurin
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Protein Kinase C
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Protein Kinase C beta
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Mitogen-Activated Protein Kinase Kinases
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bisindolylmaleimide I