All-trans Retinoic Acid Attenuates High Glucose-Induced VEGFA Expression via Inhibition of p38 MAPK and NF-κB in ARPE-19 Cells

Abstract Diabetic retinopathy (DR), a leading cause of vision loss, is characterized by retinal inflammation, vascular leakage, and pathological neovascularization, with vascular endothelial growth factor A (VEGFA) playing a central role in its progression. While anti-VEGF therapies are effective, their invasive nature and associated risks emphasize the need for safer and more accessible alternatives. This study aimed to investigate the potential of all-trans retinoic acid (RA), a bioactive metabolite of vitamin A, to suppress high glucose-induced VEGFA expression in retinal pigment epithelial (ARPE-19) cells and explore the underlying molecular mechanisms. ARPE-19 cells were treated with high glucose (30 mM) in the presence or absence of RA (5 or 20 μM). Cell viability was assessed by CCK-8 assay, while VEGFA mRNA and protein levels were measured using quantitative real-time PCR and ELISA, respectively. The activation of p38 MAPK and nuclear translocation of NF-κB p65 was evaluated through Western blot analysis. RA treatment significantly reduced high glucose-induced VEGFA expression at both the mRNA and protein levels, without affecting cell viability. Mechanistically, RA inhibited the phosphorylation of p38 MAPK and the nuclear translocation of NF-κB p65, suggesting that these pathways contribute to VEGFA regulation under hyperglycemic conditions. These findings highlight the anti-inflammatory and anti-angiogenic effects of RA in ARPE-19 cells and propose RA as a potential, safe, and non-invasive therapeutic candidate for the early intervention of diabetic retinopathy. Further in vivo studies are needed to validate its clinical applicability.