The Protective Roles of Folic Acid in Preventing Diabetic Retinopathy Are Potentially Associated with Suppressions on Angiogenesis, Inflammation, and Oxidative Stress

This study aimed to evaluate the therapeutic effect of folic acid (FA) on diabetic retinopathy (DR) in a genetic mouse model of obese type 2 diabetes mellitus (T2D). C57BL/KsJ-db/db (db/db) T2D mice were divided into control, FA, metformin (MET), and FA plus MET groups (n = 10/group). Serum levels of glucose, glycated hemoglobin, and insulin were determined weekly. The retinal thickness was measured using optical coherence tomography (OCT) at 4 weeks after treatments. The retinal expression and serum levels of vascular formation, inflammation, and oxidative stress-associated molecules were examined. Our results demonstrated that FA, but not MET, played a protective role against retinal thinning in the early stage of DR in db/db mice, although FA did not exhibit antihyperglycemic effect. In addition, retinal expression and serum levels of a panel of molecules associated with angiogenesis (CD31 and VEGFR), inflammation (IL-1β and NLRP3), and oxidative stress (3-NT, 4-HNE, Vav2, and NOX4) were significantly downregulated in FA-treated diabetic mice compared with those in saline-treated controls. Furthermore, the serum level of homocysteine was also markedly decreased following FA treatments. These findings suggest that through potential suppressions on angiogenesis, inflammation, and oxidative stress, FA may serve as a potential therapeutic agent against DR.