Suppressing endoplasmic reticulum stress-related autophagy attenuates retinal light injury

Abstract

Excessive light exposure is a principal environmental factor, which can cause damage to photoreceptors and retinal pigment epithelium (RPE) cells and may accelerate the progression of age-related macular degeneration (AMD). In this study, oxidative stress, endoplasmic reticulum (ER) stress and autophagy caused by light exposure were evaluated in vitro and in vivo . Light exposure caused severe photo-oxidative stress and ER stress in photoreceptors (661W cells) and RPE cells (ARPE-19 cells). Suppressing either oxidative stress or ER stress was protective against light damage in 661W and ARPE-19 cells and N-acetyl-L-cysteine treatment markedly inhibited the activation of ER stress caused by light exposure. Moreover, suppressing autophagy with 3-methyladenine significantly attenuated light-induced cell death. Additionally, inhibiting ER stress either by knocking down PERK signals or with GSK2606414 treatment remarkably suppressed prolonged autophagy and protected the cells against light injury. In vivo experiments verified neuroprotection via inhibiting ER stress-related autophagy in light-damaged retinas of mice. In conclusion, the above results suggest that light-induced photo-oxidative stress may trigger subsequent activation of ER stress and prolonged autophagy in photoreceptors and RPE cells. Suppressing ER stress may abrogate over-activated autophagy and protect the retina against light injury.

PERK/EIF2AK3 integrates endoplasmic reticulum stress-induced apoptosis, oxidative stress and autophagy responses in immortalised retinal pigment epithelial cells

“…Following PERK downregulation, ARPE-19 cells displayed impaired apoptosis induction associated with significant downregulation of CHOP expression. Our evidence of this protective effect corroborates previous findings which demonstrate that adenoviral-mediated PERK knockdown protects ARPE-19 cells from ER stress-associated apoptosis following hydroquinone and visible light exposure (400–800 nm)-induced ER stress via CHOP downregulation 10 , 11 . Indeed, CHOP has been shown to sensitise cells to apoptosis by downregulating gene expression of the anti-apoptotic protein Bcl-2 and upregulating pro-apoptotic Bax 22 , 33 .…”

“…PERK and its downstream signalling effectors have been shown to be essential in regulating the induction of autophagy in response to ER stress 41 . In ARPE-19 cells, autophagy can be induced by photooxidative or high-glucose environments that result in ER stress 11 , 42 . The impairment of autophagy has been extensively implicated in the ageing RPE and in the pathogenesis of AMD 24 , 43 , 44 .…”

“…RPE dysfunction is a key factor contributing to the development of age-related macular degeneration (AMD), the foremost cause of vision loss in adults in developed countries 1 , 4 – 6 . While the greatest risk factor for AMD is ageing, various environmental risk factors (cigarette smoke, light exposure) have been linked to dysregulated ER stress-dependent antioxidant responses, apoptosis and autophagy 7 – 11 . Furthermore, various proteins and protein variants associated with increased risk for developing AMD are likely contributors to ER stress and the ensuing compromised proteostasis in the RPE due to impaired intracellular trafficking, abnormal processing/accumulation/aggregation and/or reduced RPE secretion 12 – 15 .…”

Transketolase in human Müller cells is critical to resist light stress through the pentose phosphate and NRF2 pathways

“…Light-induced retinal degeneration models share many common pathogenic characteristics with AMD [ 32 ]. Models of light exposure have been used to study the regulation of retinal sphingolipids and ER stress in AMD [ 33 , 34 ]. HuPMCs with TKT knockdown were exposed to light stress to study further the roles of TKT in the Müller cells’ response to stress ( Fig.…”

Unfolded protein response alleviates acid‐induced premature senescence by promoting autophagy in nucleus pulposus cells

“…However, autophagy might be a double-edged, increasing studies revealed that prolonged autophagy may lead to cell injury (Song et al, 2020). Therefore, it is crucial to clarifying the role of autophagy in IDD.…”