Abstract
Purpose :
Glucose acts as a competitive inhibitor for vitamin C to cross the blood retinal barrier. Hyperglycemia reduces vitamin C levels in the eyes. Vitamin C acts as a cofactor for the Ten Eleven Translocation Oxidase (TET) enzymes, which are required for active DNA demethylation. Experiments were performed using primary, human retinal endothelial cells to elucidate the effects of vitamin C deficiency on the breakdown of the blood retinal barrier in diabetic retinopathy.
Methods :
Primary human retinal endothelial cells were treated either with or without 50 micromolar vitamin C and RNA was extracted. Whole transcriptome sequencing (RNA-seq) was used to determine transcription changes genome wide. Pathway analysis was performed using EnrichR, GOrilla, and Gene Set Enrichment Analysis (GSEA).
Results :
After treatment with vitamin C, 437 genes were found to have upregulated transcription and 308 genes were found to have downregulated transcription. Pathway analysis highlighted changes in several pathways that may elucidate changes that occur in retinal endothelial cells that may contribute to the pathogenesis of diabetic retinopathy, such as Insulin-like growth factor 1 (IGF-1) signaling, which was reduced after treatment with vitamin C. Although the contribution of IGF-1 to diabetic retinopathy has been largely attributed to stimulation of production of vascular endothelial growth factor A (VEGFA) in retinal pigment epithelial cells (RPE), knockout of IGF-1 receptors in retinal vascular endothelial cells was shown to reduce neovascularization in an oxygen-induced retinopathy mouse model. Additionally, VEGFA-VEGFR2 signaling pathways were reduced after treatment with vitamin C. New blood vessels from proliferative diabetic retinopathy have been found to regress after anti-VEGF treatments, and anti-VEGF is similar in efficiency to panretinal photocoagulation.
Conclusions :
These data suggest that local vitamin C deficiencies in the eyes of diabetics affect signaling in the retinal endothelial cells which may contribute to the breakdown of the blood-retinal barrier in diabetic retinopathy. Specifically, vitamin C reduces IGF-1 signaling and VEGF signaling in retinal endothelial cells.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.