IGFBPs modulate IGF-I- and high glucose-controlled growth of human retinal endothelial cells.
Insulin-like growth factor binding proteins (IGFBPs) are important local factors in the development of proliferative diabetic retinopathy. We investigated the effects of IGF-I and increased glucose concentrations on the release of IGFBPs and the growth of human retinal endothelial cells (HRECs). HRECs secrete IGFBPs-2 to -5. IGF-I stimulated thymidine incorporation and modified the pattern of IGFBPs, decreasing the inhibitory IGFBP-4 through down-regulation of its mRNA, and increasing IGFBP-5 which, per se, was able to modulate HREC growth, exerting post-transcriptional control. Studies using an antibody (alpha IR3) against the IGF-I receptor, and compounds with low affinity for IGFBPs, such as insulin and des(1-3)IGF-I, showed that an interaction between IGF-I and IGFBP-5 was necessary to detach this IGFBP from its binding sites. The dose of IGF-I that significantly decreased the IGFBP-4/IGFBP-5 ratio was the same that stimulated HREC growth. Chronic exposure to high concentrations of glucose was able to reduce HREC mitogenesis, interacting with the IGF system through a decrease in the stimulatory IGFBPs-2, -3 and -5, leaving the concentration of the inhibitory IGFBP-4 constant. These results extend our previous observations in endothelial cells and suggest that the IGFBP-4/IGFBP-5 ratio regulates IGF-I-induced growth of HRECs, whereas a general decrease in IGFBPs (except for IGFBP-4) was the anti-proliferative effect of chronic exposure to high glucose concentrations.
Giannini
S
S
Department of Clinical Pathophysiology, Endocrinology Unit, Diabetes and Metabolic Diseases Section, University of Florence, viale Pieraccini 6, 50134 Florence, Italy.
Cresci
B
B
Pala
L
L
Ciucci
A
A
Franchini
A
A
Manuelli
C
C
Fujita-Yamaguchi
Y
Y
Cappugi
P
P
Zonefrati
R
R
Rotella
C M
CM
D000704:Analysis of Variance; D001345:Autoradiography; D015152:Blotting, Northern / Q000379:methods; D015153:Blotting, Western / Q000379:methods; D002455:Cell Division / Q000187:drug effects; D002469:Cell Separation; D002478:Cells, Cultured; D003930:Diabetic Retinopathy / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D015151:Immunoblotting / Q000379:methods; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics / Q000378:metabolism; D018974:Insulin-Like Growth Factor Binding Protein 4 / Q000235:genetics / Q000378:metabolism; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000235:genetics / Q000378:metabolism; D018969:Insulin-Like Growth Factor Binding Proteins / Q000235:genetics / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis; D012171:Retinal Vessels; D013268:Stimulation, Chemical; D013936:Thymidine / Q000378:metabolism
D018971:Insulin-Like Growth Factor Binding Protein 2; D018972:Insulin-Like Growth Factor Binding Protein 3; D018974:Insulin-Like Growth Factor Binding Protein 4; D018975:Insulin-Like Growth Factor Binding Protein 5; D018969:Insulin-Like Growth Factor Binding Proteins; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D005947:Glucose; D013936:Thymidine