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 2

Retinal cellular structural changes in diabetic retinopathy.

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Retinal cellular structural changes in diabetic retinopathy. (A) Schemat...
(A) Schematic diagram of the cellular structures in a healthy neurosensory retina. There are three layers of retinal blood vessels, the SVP, intermediate capillary plexus (ICP), and deep capillary plexus (DCP) located in GCL, IPL, and OPL, respectively. Müller cells span the entire retina and interact with both neurons and vascular cells. While the somas are located in the INL, the processes extend apically surrounding inner segments of photoreceptor cells and basally approaching the vitreal surface, forming OLM and ILM, respectively. (B) In the diabetic retina, activated Müller cells exhibit hypertrophy, increased expression of GFAP, nuclear deformation, chromatin dispersion, decreased nuclear Nrf2, and increased cytoplasmic glycogen and lysosomes. Hyperglycemia stimulates the secretion of vasoactive mediators from activated Müller cells, including VEGF, ANGPT2, FGF, ANGPTL4, and TGF-β, and inflammatory cytokines, including IL-8, ICAM-1 and MCP-1, thereby promoting vascular permeability and neovascularization, stimulating retinal fibrosis, and recruiting leukocytes, ultimately contributing to chronic inflammation and neurovascular degeneration in DR. (C) Vascular cell changes, including loss of retinal pericytes, vascular endothelial cell dysfunction and death, tight junction breakdown, basement membrane thickening, and leukostasis, lead to iBRB breakdown, vascular occlusion, and neovascularization. Monocytes and neutrophils are the principal leukocyte populations that drive leukostasis. Leukocyte extravasation and iBRB breakdown mutually reinforce one another in retinal inflammation and DR, while infiltrating monocyte-derived macrophages further amplify leukostasis through the release of cytokines. (D) DR affects the morphology, function, and survival of RGCs. These changes include thinning of the RNFL, reduced RGC dendritic field sizes, irregular swelling and beading of axons, deceased branching frequency, and depleted synaptophysin.