RPE necroptosis in response to oxidative stress and in AMD

Hanus, Jakub; Anderson, Chastain; Wang, Shusheng

doi:10.1016/j.arr.2015.09.002

Cited by 218 publications

(204 citation statements)

References 124 publications

(146 reference statements)

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“…Oxidative stress, including that created by NaIO3, has been shown to induce RPE death via necroptosis, 14,17 and we postulated that this process is Fas-mediated. Our finding of reduced HMGB1 translocation in the RPE with Met12 treatment strongly supports the hypothesis that RPE necroptosis is regulated by Fas.…”

Section: Discussionmentioning

confidence: 92%

Protective Effect of Met12, a Small Peptide Inhibitor of Fas, on the Retinal Pigment Epithelium and Photoreceptor After Sodium Iodate Injury

Xiao

Yao

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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PurposeA major problem in macular degeneration is the inability to reduce RPE and photoreceptor death. These cells die by necroptosis and apoptosis, respectively, but the upstream activator(s) of these death pathways is unknown. In this study, we use the sodium iodate (NaIO3) model of oxidative stress to test the hypothesis that activation of the Fas receptor contributes to the death of the RPE and photoreceptors.MethodsSodium iodate was injected in Brown-Norway rats via femoral vein injection. Both in vivo (fundus photography, optical coherence tomography, and fluorescein angiography) and ex vivo (histology, immunohistochemistry, Western blot, and RT-PCR) analyses of the RPE and retina were conducted at baseline, as well as at various times post NaIO3 injection. The ability of intravitreal injection of Met12, a small peptide inhibitor of the Fas receptor, to prevent RPE and photoreceptor cell death was assessed.ResultsInjection of NaIO3 led to Fas-mediated activation of both necroptosis and apoptosis in the RPE and photoreceptors, respectively. This was accompanied by a significant increase in the number of microglia/macrophages in the outer retina. Met12 significantly reduced the activation of the Fas-mediated death pathways, resulting in reduced RPE and photoreceptor death and a decreased immune response.ConclusionsOur results demonstrate that NaIO3 activates Fas-mediated cell death, both in the RPE and photoreceptor, and that a small peptide antagonist of the Fas receptor, Met12, significantly reduces the extent of this cell death. These findings suggest a role for Fas inhibition to protect the RPE and photoreceptors from death due to oxidative stress.

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Section: Discussionmentioning

confidence: 92%

Protective Effect of Met12, a Small Peptide Inhibitor of Fas, on the Retinal Pigment Epithelium and Photoreceptor After Sodium Iodate Injury

Xiao

Yao

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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“…These oxidized lipids are known to increase lipofuscin production in RPE leading to photo‐sensibilization 45, inhibition of lysosomal enzymes 70 leading to an inhibition of autophagy and to an ageing of the RPE cells, all features found in AMD 71.…”

Section: Discussionmentioning

confidence: 99%

“…We have previously shown [13] that LED exposure greatly increases lipid peroxidation and HNE production at the photoreceptors segments level. These oxidized lipids are known to increase lipofuscin production in RPE leading to photo-sensibilization [45], inhibition of lysosomal enzymes [70] leading to an inhibition of autophagy and to an ageing of the RPE cells, all features found in AMD [71].…”

Section: Discussionmentioning

confidence: 99%

Effects of white light‐emitting diode (LED) exposure on retinal pigment epithelium in vivo

Jaadane

Rodriguez

Boulenguez

et al. 2017

J Cellular Molecular Medi

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Ageing and alteration of the functions of the retinal pigment epithelium (RPE) are at the origin of lost of vision seen in age‐related macular degeneration (AMD). The RPE is known to be vulnerable to high‐energy blue light. The white light‐emitting diodes (LED) commercially available have relatively high content of blue light, a feature that suggest that they could be deleterious for this retinal cell layer. The aim of our study was to investigate the effects of “white LED” exposure on RPE. For this, commercially available white LEDs were used for exposure experiments on Wistar rats. Immunohistochemical stain on RPE flat mount, transmission electron microscopy and Western blot were used to exam the RPE. LED‐induced RPE damage was evaluated by studying oxidative stress, stress response pathways and cell death pathways as well as the integrity of the outer blood–retinal barrier (BRB). We show that white LED light caused structural alterations leading to the disruption of the outer blood–retinal barrier. We observed an increase in oxidized molecules, disturbance of basal autophagy and cell death by necrosis. We conclude that white LEDs induced strong damages in rat RPE characterized by the breakdown of the BRB and the induction of necrotic cell death.

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“…Its characteristics show necrotic morphology, such as swelling organelles, and a lack of cell membrane integrity. In the latest report [52] , necroptosis has been proven to play a vital role in the pathogenesis of retinal degenerative disease. Certain ingredients in drusen, such as double-stranded RNA, may induce necroptosis in mouse RPE cells [25] .…”

Section: Discussionmentioning

confidence: 99%

Involvement of XBP1s in Blue Light-Induced A2E-Containing Retinal Pigment Epithelium Cell Death

Zhang

Zhou

et al. 2017

Ophthalmic Res

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Purpose: Retinal pigment epithelium (RPE) cell dysfunction is essential to the development of retinal degenerative disease. This study was designed to investigate how spliced X-box-binding protein 1 (XBP1s) regulates different modes of RPE cell death in vitro. Methods: Human ARPE19 cells were incubated with 25 μM N-retinylidene-N-retinylethanolamine (A2E) and irradiated with blue light. Expressions of glucose-regulated protein 78 (GRP78) and XBP1s were detected by real-time quantitative PCR and Western blot. STF-083010 was used to suppress XBP1s expression. ARPE19 cell apoptosis was assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling and flow cytometry. Receptor-interacting protein kinase-3 (RIP3) was detected by Western blot. Changes in the morphology of ARPE19 cells were identified by transmission electron microscopy. Results: Blue light-induced A2E-containing ARPE19 cell damage caused a transient elevation of GRP78 and XBP1s, while RIP3 rose in the late stage. STF-083010 effectively inhibited XBP1s expression and brought about the aggravation of apoptosis together with an alleviation of RIP3 expression. Most of the dying cells exhibited apoptotic morphology. Conclusion: A2E, along with blue light, brought about apoptosis and necroptosis of ARPE19 cells, and XBP1s was transiently elevated. The suppression of XBP1s induced ARPE19 cell death by promoting apoptosis rather than necroptosis. XBP1s might play a role in the pathogenesis of retinal degenerative diseases.

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RPE necroptosis in response to oxidative stress and in AMD

Cited by 218 publications

References 124 publications

Protective Effect of Met12, a Small Peptide Inhibitor of Fas, on the Retinal Pigment Epithelium and Photoreceptor After Sodium Iodate Injury

Protective Effect of Met12, a Small Peptide Inhibitor of Fas, on the Retinal Pigment Epithelium and Photoreceptor After Sodium Iodate Injury

Effects of white light‐emitting diode (LED) exposure on retinal pigment epithelium in vivo

Involvement of XBP1s in Blue Light-Induced A2E-Containing Retinal Pigment Epithelium Cell Death

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