Molecular stress and neurovascular injury in the diabetic retina
Chuanyu Guo, Akrit Sodhi
Chuanyu Guo, Akrit Sodhi
View: Text | PDF
Review

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

×

Figure 4

The interplay between HIFs and dysmetabolism, oxidative stress, and inflammation in diabetic retinopathy.

Options: View larger image (or click on image) Download as PowerPoint
The interplay between HIFs and dysmetabolism, oxidative stress, and infl...
(A) HIFs are heterodimeric proteins composed of an oxygen-sensitive α subunit and a ubiquitously expressed β subunit that bind to the hypoxia response element (HRE) of hypoxia-inducible genes. (B) HIF-1α and HIF-2α both contain a basic helix-loop-helix (bHLH) domain, PER-ARNT-SIM (PAS) domain, an oxygen-dependent degradation (ODD) domain, and an N-terminal and C-terminal transactivation domain (NTAD and CTAD, respectively). (C) Under normoxic conditions (left), HIF-1α and HIF-2α are hydroxylated at conserved proline residues by PHDs, marking them for recognition and degradation by the pVHL complex. Under hypoxic conditions (right), PHDs fail to hydroxylate HIF-1α and HIF-2α, allowing the proteins to accumulate, translocate to the nucleus, and activate transcription of their downstream target (hypoxia-inducible) genes. (D) In the diabetic retina, hyperglycemia stimulates oxidative stress and inflammation, stimulating accumulation of HIFs in retinal cells. Treatment with insulin can result in transient hypoglycemia that promotes increased translation and nuclear translocation of HIFs, independently of the canonical posttranslational modifications of HIFs observed in response to hypoxia. In Müller cells, accumulation of HIFs in response to hypoglycemia results in increased expression of GLUT1 and glycolytic enzymes, which promote glycolysis and lactate production. The lactate is exported through monocarboxylate transporter (MCT4) to support retinal neurons’ metabolism. However, in the diabetic retina, this physiologic response can have pathologic consequences, as increased HIF-regulated vasoactive mediators (e.g., VEGF, ANGPT2, and ANGPTL4) are also secreted from Müller cells in response to hypoglycemia. These mediators stimulate breakdown of the inner blood-retinal barrier, vessel leakage, and pathological angiogenesis. In endothelial cells, increased HIF-2α promotes expression of plasminogen activator inhibitor 1 (PAI-1) and ADORA2A. PAI-1 stimulates vascular leakage and angiogenesis, while ADORA2A induces HIF-1α accumulation, further supporting endothelial cell glycolysis and thereby promoting retinal neovascularization.