Role of Protein Kinase C on the Expression of Platelet-Derived Growth Factor and Endothelin-1 in the Retina of Diabetic Rats and Cultured Retinal Capillary Pericytes

• Published in: Diabetes (New York, N.Y.) Vol. 52; no. 3; pp. 838 - 845
• Main Authors: YOKOTA, Tamotsu, MA, Ronald C, PARK, Joong-Yeol, ISSHIKI, Keiji, SOTIROPOULOS, Konstantinos B, RAUNIYAR, Ravi K, BORNFELDT, Karin E, KING, George L
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01-03-2003
• Subjects: Aneurysms; Animals; Becaplermin; Biological and medical sciences; Blood platelets; Capillaries - chemistry; Cells, Cultured; Complications and side effects; Development and progression; Diabetes; Diabetes Mellitus, Experimental - metabolism; Diabetic retinopathy; Diabetic Retinopathy - etiology; Endothelial Growth Factors - genetics; Endothelin Receptor Antagonists; Endothelin-1 - genetics; Enzyme Activation; Enzyme Inhibitors - pharmacology; Fundamental and applied biological sciences. Psychology; Gene Expression - drug effects; Glucose; Hyperglycemia; Indoles - pharmacology; Insulin - therapeutic use; Intercellular Signaling Peptides and Proteins - genetics; Kinases; Laboratory animals; Lymphokines - genetics; Male; Maleimides - pharmacology; Metabolites; Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors; Permeability; Platelet-Derived Growth Factor - genetics; Platelet-Derived Growth Factor - pharmacology; Protein Kinase C - antagonists & inhibitors; Protein Kinase C - physiology; Protein Kinase C beta; Proteins; Proto-Oncogene Proteins c-sis - genetics; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Retina; Retina - chemistry; Retinal Vessels - chemistry; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - analysis; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; United States; Canada
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.52.3.838

Role of Protein Kinase C on the Expression of Platelet-Derived Growth Factor and Endothelin-1 in the Retina of Diabetic Rats
and Cultured Retinal Capillary Pericytes
Tamotsu Yokota 1 ,
Ronald C. Ma 1 ,
Joong-Yeol Park 1 ,
Keiji Isshiki 1 ,
Konstantinos B. Sotiropoulos 1 ,
Ravi K. Rauniyar 1 ,
Karin E. Bornfeldt 2 and
George L. King 1
1 Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts
2 Department of Pathology, School of Medicine University of Washington, Seattle, Washington
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-β 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-β 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.
Footnotes
Address correspondence and reprint requests to George L. King, Joslin Diabetes Center, Section on Vascular Cell Biology, One
Joslin Place, Boston, MA 02215. E-mail: george.king{at}joslin.harvard.edu .
Received for publication 24 May 2002 and accepted in revised form 18 November 2002.
G.L.K. is a consultant for Lilly on the PKC project..
BRPC, bovine retinal pericytes; DMEM, Dulbecco’s modified Eagle’s medium; ET-1, endothelin-1; FBS, fetal bovine serum; MAPK,
mitogen-activated protein kinase; PDGF, platelet-derived growth factor; PKC, protein kinase C; STZ, streptozotocin; VEGF,
vascular endothelial growth factor.
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