IGFBPs modulate IGF-I- and high glucose-controlled growth of human retinal endothelial cells

• Published in: Journal of endocrinology Vol. 171; no. 2; pp. 273 - 284
• Main Authors: Giannini, S, Cresci, B, Pala, L, Ciucci, A, Franchini, A, Manuelli, C, Fujita-Yamaguchi, Y, Cappugi, P, Zonefrati, R, Rotella, CM
• Format: Journal Article
• Language: English
• Published: Colchester BioScientifica 01.11.2001; Portland Press
• Subjects: Analysis of Variance; Autoradiography; Biological and medical sciences; Blotting, Northern - methods; Blotting, Western - methods; Cell Division - drug effects; Cell Separation; Cells, Cultured; Diabetic Retinopathy - metabolism; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Eye and associated structures. Visual pathways and centers. Vision; Fundamental and applied biological sciences. Psychology; Glucose - pharmacology; Humans; Immunoblotting - methods; Insulin-Like Growth Factor Binding Protein 2 - genetics; Insulin-Like Growth Factor Binding Protein 2 - metabolism; Insulin-Like Growth Factor Binding Protein 3 - genetics; Insulin-Like Growth Factor Binding Protein 3 - metabolism; Insulin-Like Growth Factor Binding Protein 4 - genetics; Insulin-Like Growth Factor Binding Protein 4 - metabolism; Insulin-Like Growth Factor Binding Protein 5 - genetics; Insulin-Like Growth Factor Binding Protein 5 - metabolism; Insulin-Like Growth Factor Binding Proteins - genetics; Insulin-Like Growth Factor Binding Proteins - metabolism; Insulin-Like Growth Factor I - pharmacology; Male; Middle Aged; Retinal Vessels; RNA, Messenger - analysis; Stimulation, Chemical; Thymidine - metabolism; Vertebrates: nervous system and sense organs; Eye; Human; Insulin like growth factor binding protein; Visual system; Endothelial cell; Growth; Blood vessel; Retina; Circulatory system; Glucose
• ISSN: 0022-0795; 1479-6805
• DOI: 10.1677/joe.0.1710273

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.