The ROCK pathway inhibitor Y-27632 mitigates hypoxia and oxidative stress-induced injury to retinal Müller cells

Purpose. Adenosine A2A receptor (A2AR) signaling is neuroprotective in some retinal damage models, but its role in neuronal survival during retinal detachment (RD) is unclear. We tested the hypothesis that A2AR antagonist ZM241385 would prevent photoreceptor apoptosis by inhibiting retinal inflammation and oxidative stress after RD. Methods. The A2AR antagonist ZM241385 was delivered daily to C57BL/6J mice for three days at a dose (3 mg/kg, i.p.) starting 2 hours prior to creating RD. A2AR expression, microglia proliferation and reactivity, glial fibrillary acidic protein (GFAP) accumulation, IL-1β expression, and reactive oxygen species (ROS) production were evaluated with immunofluorescence. Photoreceptor TUNEL was analyzed. Results. A2AR expression obviously increased and accumulated in microglia and Müller cells in the retinas after RD. The A2AR antagonist ZM241385 effectively inhibited retinal microglia proliferation and reactivity, decreased GFAP upregulation and proinflammatory cytokine IL-1β expression of Müller cells, and suppressed ROS overproduction, resulting in attenuation of photoreceptor apoptosis after RD. Conclusions. The A2AR antagonist ZM241385 is an effective suppressor of microglia proliferation and reactivity, gliosis, neuroinflammation, oxidative stress, and photoreceptor apoptosis in a mouse model of RD. This suggests that A2AR blockade may be an important therapeutic strategy to protect photoreceptors in RD and other CNS diseases that share a common etiology.

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Metabolic Imbalance Effect on Retinal Müller Glial Cells Reprogramming Capacity: Involvement of Histone Deacetylase SIRT6

Frontiers in Genetics ◽

10.3389/fgene.2021.769723 ◽

2021 ◽

Vol 12 ◽

Author(s):

L Francisco Sanhueza Salas ◽

Alfredo García-Venzor ◽

Natalia Beltramone ◽

Claudia Capurro ◽

Debra Toiber ◽

...

Keyword(s):

Oxidative Stress ◽

Histone Deacetylase ◽

Glial Cells ◽

High Glucose ◽

Müller Cells ◽

Enrichment Analysis ◽

Regulatory Elements ◽

Muller Cells ◽

Müller Glial Cells ◽

And Oxidative Stress

Retinal Müller glial cells (MGs) are among the first to demonstrate metabolic changes during retinal disease and are a potential source of regenerative cells. In response to a harmful stimulus, they can dedifferentiate acquiring neural stem cells properties, proliferate and migrate to the damaged retinal layer and differentiate into lost neurons. However, it is not yet known how this reprogramming process is regulated in mammals. Since glucose and oxygen are important regulatory elements that may help directing stem cell fate, we aimed to study the effect of glucose variations and oxidative stress in Müller cells reprogramming capacity and analyze the participation the histone deacetylase SIRT6, as an epigenetic modulator of this process. We found that the combination of high glucose and oxidative stress induced a decrease in the levels of the marker glutamine synthetase, and an increase in the migration capacity of the cells suggesting that these experimental conditions could induce some degree of dedifferentiation and favor the migration ability. High glucose induced an increase in the levels of the pluripotent factor SOX9 and a decrease in SIRT6 levels accompanied by the increase in the acetylation levels of H3K9. Inhibiting SIRT6 expression by siRNA rendered an increase in SOX9 levels. We also determined SOX9 levels in retinas from mice with a conditional deletion of SIRT6 in the CNS. To further understand the mechanisms that regulate MGs response under metabolic impaired conditions, we evaluated the gene expression profile and performed Gene Ontology enrichment analysis of Müller cells from a murine model of Diabetes. We found several differentially expressed genes and observed that the transcriptomic change involved the enrichment of genes associated with glucose metabolism, cell migration, development and pluripotency. We found that many functional categories affected in cells of diabetic animals were directly related to SIRT6 function. Transcription factors enrichment analysis allowed us to predict several factors, including SOX9, that may be involved in the modulation of the differential expression program observed in diabetic MGs. Our results underline the heterogeneity of Müller cells response and the challenge that the study of metabolic impairment in vivo represents.

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Hydrogen peroxide modulates energy metabolism and oxidative stress in cultures of permanent human Müller cells MIO-M1

Journal of Biophotonics ◽

10.1002/jbio.201600201 ◽

2016 ◽

Vol 10 (9) ◽

pp. 1180-1188 ◽

Cited By ~ 4

Author(s):

Sven Peters ◽

Max Griebsch ◽

Matthias Klemm ◽

Jens Haueisen ◽

Martin Hammer

Keyword(s):

Oxidative Stress ◽

Hydrogen Peroxide ◽

Energy Metabolism ◽

Müller Cells ◽

Muller Cells ◽

And Oxidative Stress

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Melatonin attenuates oxidative stress and inflammation of Müller cells in diabetic retinopathy via activating the Sirt1 pathway

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2021.111274 ◽

2021 ◽

Vol 137 ◽

pp. 111274

Author(s):

Yuanyuan Tu ◽

E Song ◽

Zhenzhen Wang ◽

Na Ji ◽

Linling Zhu ◽

...

Keyword(s):

Oxidative Stress ◽

Diabetic Retinopathy ◽

Müller Cells ◽

Muller Cells

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Oxidative Stress-Induced Dysfunction of Müller Cells During Starvation

Investigative Opthalmology & Visual Science ◽

10.1167/iovs.16-19275 ◽

2016 ◽

Vol 57 (6) ◽

pp. 2721 ◽

Cited By ~ 17

Author(s):

Anne Katrine Toft-Kehler ◽

Iswariaraja Scridevi Gurubaran ◽

Claus Desler ◽

Lene J. Rasmussen ◽

Dorte Marie Skytt ◽

...

Keyword(s):

Oxidative Stress ◽

Müller Cells ◽

Muller Cells

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Dietary Supplement Enriched in Antioxidants and Omega-3 Promotes Glutamine Synthesis in Müller Cells: A Key Process against Oxidative Stress in Retina

Nutrients ◽

10.3390/nu13093216 ◽

2021 ◽

Vol 13 (9) ◽

pp. 3216

Author(s):

Maryvonne Ardourel ◽

Chloé Felgerolle ◽

Arnaud Pâris ◽

Niyazi Acar ◽

Khaoula Ramchani Ben Othman ◽

...

Keyword(s):

Oxidative Stress ◽

Müller Cells ◽

Nutritional Supplement ◽

Glutamine Metabolism ◽

Muller Cells ◽

Omega 3 ◽

Glutamine Synthesis ◽

The Impact

To prevent ocular pathologies, new generation of dietary supplements have been commercially available. They consist of nutritional supplement mixing components known to provide antioxidative properties, such as unsaturated fatty acid, resveratrol or flavonoids. However, to date, only one preclinical study has evaluated the impact of a mixture mainly composed of those components (Nutrof Total®) on the retina and demonstrated that in vivo supplementation prevents the retina from structural and functional injuries induced by light. Considering the crucial role played by the glial Müller cells in the retina, particularly to regulate the glutamate cycle to prevent damage in oxidative stress conditions, we questioned the impact of this ocular supplement on the glutamate metabolic cycle. To this end, various molecular aspects associated with the glutamate/glutamine metabolism cycle in Müller cells were investigated on primary Müller cells cultures incubated, or not, with the commercially mix supplement before being subjected, or not, to oxidative conditions. Our results demonstrated that in vitro supplementation provides guidance of the glutamate/glutamine cycle in favor of glutamine synthesis. These results suggest that glutamine synthesis is a crucial cellular process of retinal protection against oxidative damages and could be a key step in the previous in vivo beneficial results provided by the dietary supplementation.

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Notoginsenoside R1 Ameliorates Diabetic Retinopathy through PINK1-Dependent Activation of Mitophagy

Cells ◽

10.3390/cells8030213 ◽

2019 ◽

Vol 8 (3) ◽

pp. 213 ◽

Cited By ~ 15

Author(s):

Ping Zhou ◽

Weijie Xie ◽

Xiangbao Meng ◽

Yadong Zhai ◽

Xi Dong ◽

...

Keyword(s):

Oxidative Stress ◽

Diabetic Retinopathy ◽

Oral Treatment ◽

Müller Cells ◽

Panax Notoginseng ◽

Protective Effects ◽

Muller Cells ◽

Beneficial Effects ◽

Pre Treatment ◽

Lc3 Puncta

: Accumulating evidence has indicated that inflammation, oxidative stress, apoptosis, and autophagy in retinal Müller cells are involved in diabetic retinopathy (DR). Notoginsenoside R1 (NGR1), a novel saponin extracted from Panax notoginseng, posesses pharmacological properties, including treating diabetic encephalopathy and improving microcirculatory disorders. Nevertheless, its beneficial effects on DR and the potential mechanism remain to be elucidated. In this study, we found retinal vascular degeneration, reduced retinal thickness, and impaired retinal function in db/db mice were all dramatically attenuated by oral treatment with NGR1 (30 mg/kg) for 12 weeks. NGR1 pretreatment also significantly inhibited apoptosis, markedly suppressed the VEGF expression, markedly increased PEDF expression and markedly inhibited oxidative stress and inflammation in rat retinal Müller cells (rMC-1) subjected to high glucose (HG) and in the retinas of db/db mice. Furthermore, NGR1 pre-treatment upregulated the level of PINK1 and Parkin, increased the LC3-II/LC3-I ratio, and downregulated the level of p62/SQSTM1 in rMC-1 cells induced by HG and in the retinas of db/db mice. Moreover, NGR1 administration enhanced the co-localization of GFP-LC3 puncta and MitoTracker in rMC-1 cells. Importantly, knockdown of PINK1 abolished the protective effects of NGR1. In conclusion, these phenomena suggested that NGR1 prevented DR via PINK1-dependent enhancement of mitophagy.

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