Diabetic Retinopathy: New Treatment Approaches Targeting Redox and Immune Mechanisms

Abstract

Diabetic retinopathy (DR) represents a severe complication of diabetes mellitus, characterized by irreversible visual impairment resulting from microvascular abnormalities. Since the global prevalence of diabetes continues to escalate, DR has emerged as a prominent area of research interest. The development and progression of DR encompass a complex interplay of pathological and physiological mechanisms, such as high glucose-induced oxidative stress, immune responses, vascular endothelial dysfunction, as well as damage to retinal neurons. Recent years have unveiled the involvement of genomic and epigenetic factors in the formation of DR mechanisms. At present, extensive research explores the potential of biomarkers such as cytokines, molecular and cell therapies, antioxidant interventions, and gene therapy for DR treatment. Notably, certain drugs, such as anti-VEGF agents, antioxidants, inhibitors of inflammatory responses, and protein kinase C (PKC)-β inhibitors, have demonstrated promising outcomes in clinical trials. Within this context, this review article aims to introduce the recent molecular research on DR and highlight the current progress in the field, with a particular focus on the emerging and experimental treatment strategies targeting the immune and redox signaling pathways.

Keywords: anti-VEGF drugs; corticosteroids; diabetic retinopathy; epigenetic changes; oxidative stress; reactive oxygen species.

Figure 1

Overview of the molecular structure and mechanism of action of NOX, as well as regarding mitochondrial dysfunction and ROS generation. FAD: flavin adenine dinucleotide; Fe: heme group containing Fe atom; NADPH: nicotinamide adenine dinucleotide phosphate; NOX: NADPH oxidase; O₂: oxygen; O₂^•−: superoxide anion; ROS: reactive oxygen species.

Figure 2

Schematic representation of the pathogenesis of DR leading to a disruption of the redox homeostasis in the eye. Hyperglycemia triggers oxidative stress responses through multiple pathways, ultimately leading to DR. In this context, PKC inhibitors, NOX inhibitors, and antioxidant agents antagonize the effect of oxidative stress. AGE: advanced glycation end products; GlcNAc-6-P: N-acetylglucosamine 6-phosphate; GSH: glutathione; H₂O₂: hydrogen peroxide; PKC: protein kinase C; NADPH: nicotinamide adenine dinucleotide phosphate; NOX: nicotinamide adenine dinucleotide phosphate oxidase; O₂^•−: superoxide anion; MnSOD: manganese superoxide dismutase.

Figure 3

Illustration of the leukocyte recruitment along the endothelium and extravasation, as well as of the leukocyte activation in diabetic retinopathy. IL-1β: interleukin-1 beta; MCP-1: monocyte chemoattractant protein-1; NF-kB: nuclear factor kappa-light-chain-enhancer of activated B cells; TNF-α: tumor necrosis factor alpha; VAP-1: vascular adhesion protein-1; VCAM-1: vascular cell adhesion molecule-1.

Figure 4

Oxidative stress activates various pathogenetic events. In terms of blood vessels, retinal endothelial cell damage, changes in retinal blood flow pattern, and glial dysfunction will all promote increases in vascular permeability, ischemia, and hypoxia and lead to insufficient perfusion, and eventually induce neoangiogenesis. Parallelly, processes of inflammation and apoptosis lead to chronic immune reactivity and to loss of neural cells. ECM: extracellular matrix; ICAM-1: intercellular adhesion molecule-1; IL-1β: interleukin-1 beta; IL-6: interleukin-6; iNOS: nitric oxide synthases; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; ROS: reactive oxygen species; TNF-α: tumor necrosis factor alpha; VEGF: vascular endothelial growth factor.

Figure 5

The IL-6 signaling pathway and the mechanism of action of tolicizumab. Through a receptor composed of signal transduction subunit glycoprotein 130 (gp130) and the auxiliary transmembrane protein IL-6 receptor (IL-6R), IL-6 activates the JAK/STAT axis, while the MAPK cascade and the PI3K/Akt axis are activated by the domain SHP2. Tolicizumab antagonizes the subunit gp130. Akt: Ak strain transforming (also known as protein kinase B, PKB); IL-6: interleukin-6; IL-6R: IL-6 receptor; gp130: glycoprotein 130; JAK: Janus kinase; MAPK: mitogen-activated protein kinase; PI3K: phosphoinositide 3-kinases; SHP2: src homology phosphotvrosvlphosphatase 2; STAT: signal transducer and activator of transcription.