Oxidative stress and autophagy-related changes during retinal degeneration and development

Abstract

Retinitis pigmentosa (RP) is an inherited retinopathy that leads to photoreceptor loss. RP has been related to oxidative stress, autophagy, and inflammation. This study aimed to identify changes in the levels of oxidative stress and autophagy markers in the retina of control and rd10 mice during different phases of retinal development. Changes in the retinal oxidation system were investigated by measuring the levels of oxidized and reduced glutathione (GSH/GSSG), retinal avidin-positive cells, and 4-hydroxynonenal (4-HNE) staining intensity. Autophagy characterization was explored by measuring the levels of microtubule-associated protein 1 light chain 3 (LC3), beclin, autophagy-related proteins 5 and 7 (Atg5 and Atg7), and lysosomal associated membrane protein-2A (LAMP-2A). At P28 retinal GSH concentrations decreased in rd10 mice compared to the controls. No differences were found in retinal GSSG concentrations between the control and rd10 mice. There was an increase in retinal GSSG concentrations and a decrease in the GSH/GSSG ratio in the control and rd10 mice at P21 and P28 compared to P13. We observed an increase in avidin-positive cells in rd10 retinas. 4-HNE was increased in rd10 retinas at P13, and it also increased in control mice with age. We did not observe any differences in the retinal levels of LC3II/I ratio, Beclin, Atg5, or Atg7 in the rd10 mice compared to the controls. There was an increase in the LAMP-2A concentrations in the control and rd10 mice with development age (P28 concentrations vs. P13). Although only slight differences were found in the oxidative stress and autophagy markers between the control and rd10 mice, there were increases in the GSSG, 4-HNE, and LAMP-2A with age. This increase in the oxidative stress and chaperone-mediated autophagy has not been described before and occurred just after the mice opened their eyes, potentially indicating a retinal response to light exposure.

Combination Antioxidant/NSAID Therapies and Oral/Topical Ocular Delivery Modes for Prevention of Oxygen-Induced Retinopathy in a Rat Model

“…Two important synaptic interactions occur at the time of eye opening, the splitting of the visual signal into two channels for light and dark objects and the instillation of pathways to create simultaneous contrast of visual objects [ 70 ]. Our findings support previous reports and provide further evidence for a role of GSH in retinal development [ 71 ]. Exposure to IH substantially delayed eye opening in a large percentage of rats in all groups (28–67%), and, in the case of nGSH, only 33% opened their eyes on P14, suggesting delayed retinal neural circuitry and visual cortex maturation.…”

The Relevance of Oxidative Stress in the Pathogenesis and Therapy of Retinal Dystrophies

“…Several studies show that both endogenous OS produced during retinal metabolism, such as lipid peroxidation or DNA damage, and exogenous OS, such as those produced by sunlight exposition, contribute to photoreceptor cell death. Moreover, rod photoreceptor death cause that higher levels of oxygen permeate into the tissue, thus increasing ROS production and inducing cell oxidative damage into the surviving cells (mostly cones), which will eventually result in cone death [17,95,96]. Since the retina is a highly-metabolic demanding tissue, retinal cells have developed protective mechanisms against damaging agents, among them, autophagy activation.…”

Gradual Increase in Environmental Light Intensity Induces Oxidative Stress and Inflammation and Accelerates Retinal Neurodegeneration

“…As a consequence of this photoreceptor cell death, there is an increase of the retinal inflammatory state due to the activation of microglia, which also exacerbates retinal degeneration. 10 Many studies suggest that the death of rod photoreceptors is accompanied by an increase of retinal oxygen levels 11 and reactive oxygen species (ROS) from different sources. 12,13 This contributes to the increment of oxidative stress and exacerbates rod degeneration.…”

“…Many studies suggest that the death of rod photoreceptors is accompanied by an increase of retinal oxygen levels 11 and reactive oxygen species (ROS) from different sources. 12 , 13 This contributes to the increment of oxidative stress and exacerbates rod degeneration.…”