Abstract
Purpose :
Diabetic retinopathy (DR) is the leading cause of blindness in the working-age population. High glucose is thought to be the primary cause of DR, however, the precise mechanism remains to be clarified. Protein O-GlcNAcylation modification has been shown to act as a nutrient sensor that is particularly sensitive to ambient glucose. This study aimed to explore the role of protein O-GlcNAcylation in DR and its mechanism.
Methods :
Western blot and immunofluorescence staining were used to evaluate protein O-GlcNAcylation level in DR patients, oxygen-induced retinopathy mouse model, and streptozocin-induced diabetes mouse model. Endothelial-specific knockout animal models and pharmacological inhibitors were used to study the effects of O-GlcNAcylation in retinal angiogenesis. Proteomic analysis, RNA sequencing, and multiple molecular biological techniques were employed to explore the mechanism.
Results :
We found that protein O-GlcNAcylation level was increased in endothelial cells in the retina of DR patients and mouse models. Endothelial-specific depletion or pharmacological inhibition of O-GlcNAc transferase (OGT), the key enzyme responsible for adding GlcNAc moieties to target proteins, significantly suppressed pathological angiogenesis. Mechanistically, we found that the ultimate effectors of Hippo pathway, YAP and TAZ, could be O-GlcNAcylated upon high glucose stimulation and thus hyperactivated and stabilized. The highly activated YAP/TAZ promoted pathological angiogenesis by inducing a pro-angiogenic transcriptional program in endothelial cells. Targeting OGT-YAP/TAZ axis showed therapeutic potential in treating DR.
Conclusions :
Collectively, these findings identify a critical role for O-GlcNAcylation modification in DR and suggest a unique potential for targeting GlcNAcylation signaling in DR therapy.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.