Inhibition by advanced glycation end products (AGEs) of pigment epithelium-derived factor (PEDF) gene expression in microvascular endothelial cells

Pigment epithelium-derived factor (PEDF) is a natural extracellular component of the retina with neuronal differentiating activity. Recently, decreased levels of PEDF in the mammalian eye have been shown to participate in the pathogenesis of diabetic retinopathy. In addition, advanced glycation end products (AGEs), senescent macroprotein derivatives that form at an accelerated rate under diabetes, have also been implicated in the development and progression of diabetic retinopathy. However, the role of AGEs in decreased levels of PEDF in the eye remains to be elucidated. In this study, we examined the effects of AGEs on PEDF gene expression in microvascular endothelial cells (ECs). Various types of immunochemically distinct AGEs, which were prepared in vitro by incubating bovine serum albumin with glucose, glyceraldehyde or glycolaldehyde, significantly decreased endothelial mRNA levels of PEDF. Furthermore, H₂O₂ dose-dependently suppressed PEDF gene expression in ECs. Our present results suggest that AGEs could down-regulate mRNA levels of PEDF in ECs, probably via oxidative stress generation. The deleterious effects of AGEs on diabetic retinopathy could be due, at least in part, to their PEDF-inhibitory properties.