Polyphenol metabolite pyrogallol-o-sulfate decreases microglial activation and vegf in retinal pigment epithelium cells and diabetic mouse retina

Abstract

Funding Information: The authors acknowledge Fundacao para a Ciencia e Tecnologia for funding (PD/BD/114251/2016 scholarship to D.F. Santos; EXPL-BIM-MEC-1433-2013; PTDC/BTM/ORG/28121/2017 grants to G.A.Silva) and iNOVA4Health ? UIDB/Multi/04462/2020, a program financially supported by Funda??o para a Ci?ncia e Tecnologia/Ministerio da Educacao e Ciencia through national funds and co-funded by FEDER under the PT2020 Partnership Agreement, is also acknowledged. C.N.S. also acknowledges the European Research Council (ERC) under the European Union?s Horizon 2020 Research and Innovation Programme under Grant Agreement No. 804229. Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.(Poly)phenol-derived metabolites are small molecules resulting from (poly)phenol metab-olization after ingestion that can be found in circulation. In the last decade, studies on the impact of (poly)phenol properties in health and cellular metabolism accumulated evidence that (poly)phenols are beneficial against human diseases. Diabetic retinopathy (DR) is characterized by inflammation and neovascularization and targeting these is of therapeutic interest. We aimed to study the effect of pyrogallol-O-sulfate (Pyr-s) metabolite in the expression of proteins involved in retinal glial acti-vation, neovascularization, and glucose transport. The expression of PEDF, VEGF, and GLUT-1 were analyzed upon pyrogallol-O-sulfate treatment in RPE cells under high glucose and hypoxia. To test its effect on a diabetic mouse model, Ins2Akita mice were subjected to a single intraocular injection of the metabolite and the expression of PEDF, VEGF, GLUT-1, Iba1, or GFAP measured in the neural retina and/or retinal pigment epithelium (RPE), two weeks after treatment. We observed a significant decrease in the expression of pro-angiogenic VEGF in RPE cells. Moreover, pyrogallol-O-sulfate significantly decreased the expression of microglial marker Iba1 in the diabetic retina at different stages of disease progression. These results highlight the potential pyrogallol-O-sulfate metabolite as a preventive approach towards DR progression, targeting molecules involved in both inflammation and neovascularization.publishersversionpublishe