Can polyphenols’ metabolites ameliorate the outcome of Diabetic Retinopathy?

• Autor(a) principal: Pais, Mariana de Abreu Gomes
• Data de Publicação: 2018
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10362/51109
• topic: Diabetes Mellitus; Diabetic Retinopathy; angiogenesis; inflammation; phenolic metabolites; Domínio/Área Científica::Engenharia e Tecnologia::Engenharia Química

The prevalence of Diabetes Mellitus worldwide continues to increase and Diabetic Retinopathy (DR), a blood-retinal barrier disorder, is its most common ocular complication in developed countries. Chronic exposure to hyperglycemia and hypoxia is essential to the pathophysiology of DR, that in advanced stages leads to neovascularization and consequently vision loss. There is no cure for DR, only symptomatic care with invasive treatments, such as laser photocoagulation, which have several drawbacks, and anti-VEGF (vascular endothelial growth factor) therapies, which do not halt the progression of the disease. Several studies report an imbalance between pro-angiogenic and anti-angiogenic factors, which promotes the pathological angiogenesis characteristic of DR. It was also reported that patients with DR have physiological changes consistent with chronic inflammation. Since abnormal angiogenesis and chronic inflammation are considered important hallmarks of DR, it is critical to develop efficient therapies. Phenolic metabolites have been used in several disease paradigms due to its potential therapeutic effect. It is reported that Cathecol-O-sulfate (Cat-sulf) and Pyrogallol-O-sulfate (Pyr-sulf) were shown to reduce inflammation markers and cross blood brain barrier in in vitro models. Therefore, the aim of this study is to evaluate the effect of Cat-sulf and Pyr-sulf in the expression of pro- and anti-angiogenic markers, in the expression of retina glucose transporter (GLUT1) and in inflammation biomarkers. In vitro, using a retinal cell line, and in vivo, using a mouse model of DR. Our results show that in the tested concentrations, Cat-sulf had a negative influence on the viability of D407 RPE cells and was excluded for the rest of this study. For Pyr-sulf our results have shown a positive effect on cell viability and it increases the mRNA levels of the PEDF (Pigment Epithelium–Derived Factor) and decreases VEGF protein expression under diabetic conditions. It is well known that in diabetic conditions the expression of the GLUT1 is increased. Treatment with Pyr-sulf, although not statistically significant, decreases GLUT1 expression under diabetic conditions in D407 RPE cells, highlighting the beneficial effect of this phenolic metabolite in controlling glucose transport. Furthermore, in RPE cells treated with Pyr-sulf the expression of inflammatory markers under hypoxic conditions decreases, confirming the anti-inflammatory effect of this phenolic metabolite. To support our in vitro studies, we have shown that in Ins2Akita mice, a model for type I diabetes and DR, Pyr-sulf decreases the expression of the pro-inflammatory protein Iba1. Taken together, these results shown the great potential of Pyr-sulf as treatment for diseases associated with chronic inflammation and abnormal angiogenesis, such as DR.