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

Insulin-like growth factor binding proteins (IGFBPs) are important local fa ctors in the development of proliferative diabetic retinopathy. We investig ated the effects of IGF-I and increased glucose concentrations on the relea se of IGFBPs and the growth of human retinal endothelial cells (HRECs). HRE Cs secrete IGFBPs-2 to -5. IGF-I stimulated thymidine incorporation and mod ified 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 1R3)against the IGF-I receptor, and compounds with low a ffinity for IGFBPs, such as insulin and des(1-3)IGF-I, showed that an inter action between IGF-I and IGFBP-5 was necessary to detach this IGFBP from it s 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 t o high concentrations of glucose was able to reduce HREC mitogenesis, inter acting with the IGF system through a decrease in the stimulatory IGFBPs-2, -3 and -5, leaving the concentration of the inhibitory IGFBP-4 constant. Th ese results extend our previous observations in endothelial cells and sugge st 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-prol iferative effect of chronic exposure to high glucose concentrations.