Molecular stress and neurovascular injury in the diabetic retina
Chuanyu Guo, Akrit Sodhi
Chuanyu Guo, Akrit Sodhi
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Molecular stress and neurovascular injury in the diabetic retina

Abstract

Diabetic retinopathy (DR), the most common microvascular complication in patients with diabetes mellitus (DM), is a leading cause of vision loss worldwide. Sustained hyperglycemia plays a central role in promoting DR. However, tight glycemic control does not prevent — and indeed sometimes worsens — DR, highlighting the importance of ongoing studies aimed at improving our understanding of this complex disease. Over the last few decades, the dogma that DR is a vascular disease that results in secondary neuronal injury has evolved, as emerging evidence suggests that neurodegeneration occurs in parallel with or prior to vascular cell injury in the retina of patients with DM. This has led to appreciation of DR as a neurovascular disease, characterized by microvascular injury and neurodegeneration, both of which contribute to vision loss. Here, we explore how molecular stress (i.e., glucose dysregulation, dysmetabolism, oxidative stress, and inflammation) promote retinal vascular cell and neuronal injury in patients with DM. We focus on how these processes influence, and are influenced by, genes regulated by the HIF family of transcription factors in glial, vascular, neuronal, and inflammatory cells, with the goal of identifying new therapeutic avenues for the prevention or early treatment of patients with this vision-threating disease.

Authors

Chuanyu Guo, Akrit Sodhi

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Figure 3

Pathological process in diabetic retinopathy.

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Pathological process in diabetic retinopathy. (A) Schematic diagram of d...
(A) Schematic diagram of dysmetabolism in response to high glucose. Aldose reductase (AR), a key enzyme in the polyol pathway, converts glucose into sorbitol, a highly hydrophilic sugar alcohol that is difficult to metabolize and accumulates in cells, contributing to glial cell activation, pericyte apoptosis, and endothelial cell death. Uridine diphosphate–N-acetylglucosamine (UDP-GlcNAc), produced via the hexosamine biosynthetic pathway, is the donor for O-GlcNAcylation, which mediates hyperglycemia-induced RGC death, impairs pericyte migration, and promotes retinal pericyte apoptosis. Increased protein kinase C (PKC) activity in retinal endothelial cells in diabetic retina induces pericyte apoptosis and acellular capillaries. AGEs stimulate pericyte apoptosis, angiogenesis, and breakdown of the iBRB. (B) High glucose enhances ROS accumulation while suppressing GSH expression in the retina, leading to oxidative stress and injury to the retinal microvasculature and neurons, including angiogenesis, iBRB breakdown, loss of RGCs, activation of Müller cells, activation of microglia, and damage to photoreceptors. High glucose also upregulates STING, which initiates the expression of inflammatory genes through NF-κB. In patients with DR, ocular tissues exhibit elevated levels of proinflammatory cytokines (IL-6, IL-1β, IL-8, TNF-α), chemokines (CCL-2/MCP-1, CXCL1), adhesion molecules (ICAM-1, VCAM-1), and growth factors (VEGF, TGF-β), which further promote injury to the retinal microvasculature and neurons.