Antiangiogenic cytokines as potential new therapeutic targets for resveratrol in diabetic retinopathy

Mihaela Popescu,1 Cătălina Bogdan,2 Adela Pintea,3 Dumitriţa Rugină,3 Corina Ionescu1 1Department of Biochemistry, University of Medicine and Pharmacy “Iuliu Haţieganu”, Cluj-Napoca, Romania; 2Department of Dermopharmacy and Cosmetics, University of Medicine and Pharmacy “Iuliu Haţieganu”, Cluj-Napoca, Romania; 3Department of Biochemistry, University of Agriculture Sciences and Veterinary Medicine, Cluj-Napoca, Romania Abstract: Diabetes mellitus (DM) affects >350 million people worldwide. With many complications that can reduce the patient’s quality of life, vision loss is one of the most debilitating disorders it can cause. Active research in the field of diabetes includes microvascular complications in diabetic retinopathy (DR). Disturbances in the balance of pro-angiogenesis and anti-angiogenesis factors can lead to the progression of DR. The retinal pigment epithelium (RPE) is the outermost layer of the retina, and it is essential in maintaining the visual function. The RPE produces and secretes growth factors as well as protective agents which maintain structural integrity of the retina. Small natural molecules, such as resveratrol, may influence neurotrophic factors of the retina. The pigment epithelium-derived factor (PEDF) and thrombospondin-1 (TSP-1) are secreted by RPE cells. These two proteins inhibit angiogenesis and inflammation in RPE cells. An alteration of their production contributes to various eye diseases. There is a critical balance between two important factors secreted on opposite sides of the RPE: at the basal side, vascular endothelial growth factor (VEGF; acts on the choroidal endothelium) and, on the apical side, PEDF (acts on neurons and photoreceptors). Resveratrol inhibits VEGF expression in human adult RPE cells and limits the development of proliferative vitreoretinopathy, by attenuating transforming growth factor-β2-induced wound closure and cell migration. Possible new mechanisms could include PEDF and TSP-1 expression alterations under physiological and pathological conditions. Resveratrol is currently of interest due to its capacity to influence the cell’s secretory activity. Some limitations arise from its low bioavailability. Several drug delivery systems are currently tested, promising to improve tissue concentrations. This article reviews biological pathways involved in the pathogenesis of DR that could be influenced by resveratrol. A study of these pathways could identify new potential targets for the reduction of diabetic complications. Keywords: diabetes, retinal secretome, diabetic microvascular complications, phytoalexi