Oxidative Stress as the Main Target in Diabetic Retinopathy Pathophysiology

Olvera-Montaño Cecilia, Castellanos-González José Alberto, Navarro-Partida José, Cardona-Muñoz Ernesto Germán, López-Contreras Ana Karen, Roman-Pintos Luis Miguel, Robles-Rivera Ricardo Raúl, Rodríguez-Carrizalez Adolfo Daniel, Olvera-Montaño Cecilia, Castellanos-González José Alberto, Navarro-Partida José, Cardona-Muñoz Ernesto Germán, López-Contreras Ana Karen, Roman-Pintos Luis Miguel, Robles-Rivera Ricardo Raúl, Rodríguez-Carrizalez Adolfo Daniel

Abstract

Diabetic retinopathy (DR) is one of the most common complications of diabetes mellitus (DM) causing vision impairment even at young ages. There are numerous mechanisms involved in its development such as inflammation and cellular degeneration leading to endothelial and neural damage. These mechanisms are interlinked thus worsening the diabetic retinopathy outcome. In this review, we propose oxidative stress as the focus point of this complication onset.

Conflict of interest statement

Authors declare that they have no conflicts of interest to report.

Figures

Figure 1
Figure 1
Damage at each retinal layer. A series of events occur in early DR development. Neurodegeneration of horizontal, bipolar, amacrine, and ganglion cells. These damages may be determined by proNGF concentrations as NLRP3 and NLRP1 are related to eye degenerative diseases. NFL: nerve fiber layer; GCL: ganglion cell layer; IPL: inner plexiform layer; INL: inner nuclear layer; ∗OPL: outer plexiform layer; ONL: outer nuclear layer; PL: photoreceptor layer.
Figure 2
Figure 2
Glucose metabolic pathways in the hyperglycemic milieu, oxidative stress in diabetic retinopathy, and antioxidant targets. In hyperglycemic states, different pathways were activated producing ROS which enhance inflammatory, apoptotic, and degeneration pathways, ultimately leading to the appearance of diabetic retinopathy clinical characteristics. Some antioxidant substances are able to interact with ROS (xanthophylls, vitamins C and E, and anthocyanin); others function as cofactors to enhance antioxidant enzymes (Cu, Zn, and vitamins E and C), and others are capable of inhibiting the expression of proinflammatory and prodegeneration factors (curcumin and lutein). Finally, all of them interfere in diabetic retinopathy development.
Figure 3
Figure 3
The ROS role in inflammation and pyroptosis. ROS augments NF-κB production which promotes proinflammatory mediators favoring the expression of VEGF. VEGF translocates NF-κB into the nucleus, and NF-κB activate NLRP3 with caspase cleavage leading to cytokine release. NLRP3 inflammasome has been associated to diabetic retinopathy by Müller pyroptosis by the caspase-1/IL-1beta pathway. NF-κB: nuclear factor kappa B; COX-2: cyclooxygenase-2; VEGF: vascular endothelial growth factor.
Figure 4
Figure 4
The ROS role in autophagy. ROS upregulate MMP9 and MMP2 that leads to mitochondrial membrane potential impairment. When a mithochondrion malfunctions, autophagy (mitophagy) is activated, though in high stress conditions, caspases inactivate mitophagy and activate apoptosis pathways.
Figure 5
Figure 5
The ROS role in neurodegeneration. In physiological conditions, NGF activates VEGF to promote angiogenesis and protect nerves from hypoxia and ROS inhibits NGF formation from its precursor which leads to neural apoptosis. ROS activate ZNRF1 that provokes neurodegeneration; at the same time, TNF-α activates apoptosis via metalloproteinase/caspase pathway. ZNRF1: zinc and ring finger-1; NGF: nerve growth factor; VEGF: vascular endothelial growth factor; MMP: matrix metalloproteinases; TNF-α: tumor necrosis factor-α.

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