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.
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.
Yokota
Tamotsu
T
Research Division, Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA 02215, USA.
Ma
Ronald C
RC
Park
Joong-Yeol
JY
Isshiki
Keiji
K
Sotiropoulos
Konstantinos B
KB
Rauniyar
Ravi K
RK
Bornfeldt
Karin E
KE
King
George L
GL
D000818:Animals; D000077214:Becaplermin; D002196:Capillaries / Q000737:chemistry; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003930:Diabetic Retinopathy / Q000209:etiology; D016228:Endothelial Growth Factors / Q000235:genetics; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000235:genetics*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology; D007328:Insulin / Q000627:therapeutic use; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D008222:Lymphokines / Q000235:genetics; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D010982:Platelet-Derived Growth Factor / Q000235:genetics* / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D064546:Protein Kinase C beta; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D012160:Retina / Q000737:chemistry*; D012171:Retinal Vessels / Q000737:chemistry*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D007211:Indoles; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D008301:Maleimides; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C075278:platelet-derived growth factor A; D000077214:Becaplermin; C099154:ruboxistaurin; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D020929:Mitogen-Activated Protein Kinase Kinases; C070515:bisindolylmaleimide I