The Complex Relationship between Diabetic Retinopathy and High-Mobility Group Box: A Review of Molecular Pathways and Therapeutic Strategies

Abstract

High-mobility group box 1 (HMGB1) is a protein that is part of a larger family of non-histone nuclear proteins. HMGB1 is a ubiquitary protein with different isoforms, linked to numerous physiological and pathological pathways. HMGB1 is involved in cytokine and chemokine release, leukocyte activation and migration, tumorigenesis, neoangiogenesis, and the activation of several inflammatory pathways. HMGB1 is, in fact, responsible for the trigger, among others, of nuclear factor-κB (NF-κB), tumor necrosis factor-α (TNF-α), toll-like receptor-4 (TLR-4), and vascular endothelial growth factor (VEGF) pathways. Diabetic retinopathy (DR) is a common complication of diabetes mellitus (DM) that is rapidly growing in number. DR is an inflammatory disease caused by hyperglycemia, which determines the accumulation of oxidative stress and cell damage, which ultimately leads to hypoxia and neovascularization. Recent evidence has shown that hyperglycemia is responsible for the hyperexpression of HMGB1. This protein activates numerous pathways that cause the development of DR, and HMGB1 levels are constantly increased in diabetic retinas in both proliferative and non-proliferative stages of the disease. Several molecules, such as glycyrrhizin (GA), have proven effective in reducing diabetic damage to the retina through the inhibition of HMGB1. The main focus of this review is the growing amount of evidence linking HMGB1 and DR as well as the new therapeutic strategies involving this protein.

Adiponectin Ameliorates Hyperglycemia-Induced Retinal Endothelial Dysfunction, Highlighting Pathways, Regulators, and Networks

“…Intravitreal injection of HMGB1 mimics the effects of diabetes and increases RAGE, ERK1/2, NF-κB, and proinflammatory biomarkers such as ICAM-1 and soluble ICAM-1. 33 The binding of RAGEs enhances the transcriptional activity of NF-κB, induces the significant upregulation of IL-1β and ROS in HRMECs increases retinal vascular permeability, and disrupts the stability of tight junction complex between adjacent retinal microvascular EC via decreased TLR-2 and occludin expression. 34 These studies demonstrate the critical role of HMGB1 in the pathogenesis of diabetic retinopathy.…”

Clinical and Molecular-Genetic Insights into the Role of Oxidative Stress in Diabetic Retinopathy: Antioxidant Strategies and Future Avenues

“…In our opinion, the possibility remains that biotherapies based on the redox changes occurring in diabetics may help to protect the retina. In the latter concern, an interesting spectrum of presumptive factors for DR protection has been ultimately proposed, including outstanding antioxidants [ 50 , 51 , 52 , 53 ].…”

Diabetic retinopathy, oxidative stress, and sirtuins: an in depth look in enzymatic patterns and new therapeutic horizons

“…76 High mobility group box 1 (HMGB1) is a transcription supporting protein mainly localized in the nucleus that is involved in inflammatory pathways, RECs apoptosis in RD, and the breakdown of BRB. 92 HMGB1 triggers the activation of RAGE and toll-like receptors that leads to the transcription of NF-κB. HMGB1 is upregulated in the vitreous and epiretinal membranes in patients with PDR.…”