Title:Retinal Protein O-GlcNAcylation and the Ocular Renin-angiotensin System: Signaling Cross-roads in Diabetic Retinopathy
Volume: 18
Issue: 2
Author(s): Sadie K. Dierschke and Michael D. Dennis*
Affiliation:
- Department of Cellular and Molecular Physiology, H166, Penn State College of Medicine, 500 University Drive Hershey,
PA 17033, USA
- Department of Ophthalmology, Penn State College of Medicine, 500 University Drive Hershey, PA 17033, USA
Keywords:
Diabetes, retinopathy, O-GlcNAcylation, mRNA translation, renin-angiotensin system, oxidative stress, inflammation.
Abstract: It is well established that diabetes and its associated hyperglycemia negatively impact
retinal function, yet we know little about the role played by augmented flux through the Hexosamine
Biosynthetic Pathway (HBP). This offshoot of the glycolytic pathway produces UDP-Nacetyl-
glucosamine, which serves as the substrate for post-translational O-linked modification of
proteins in a process referred to as O-GlcNAcylation. HBP flux and subsequent protein O-GlcNAcylation
serve as nutrient sensors, enabling cells to integrate metabolic information to appropriately
modulate fundamental cellular processes including gene expression. Here we summarize the impact
of diabetes on retinal physiology, highlighting recent studies that explore the role of O-GlcNAcylation-
induced variation in mRNA translation in retinal dysfunction and the pathogenesis of Diabetic
Retinopathy (DR). Augmented O-GlcNAcylation results in wide variation in the selection of
mRNAs for translation, in part, due to O-GlcNAcylation of the translational repressor 4E-BP1. Recent
studies demonstrate that 4E-BP1 plays a critical role in regulating O-GlcNAcylation-induced
changes in the translation of the mRNAs encoding Vascular Endothelial Growth Factor (VEGF), a
number of important mitochondrial proteins, and CD40, a key costimulatory molecule involved in
diabetes-induced retinal inflammation. Remarkably, 4E-BP1/2 ablation delays the onset of diabetes-
induced visual dysfunction in mice. Thus, pharmacological interventions to prevent the impact
of O-GlcNAcylation on 4E-BP1 may represent promising therapeutics to address the development
and progression of DR. In this regard, we discuss the potential interplay between retinal
O-GlcNAcylation and the ocular renin-angiotensin system as a potential therapeutic target of future
interventions.
