High glucose treatment promotes extracellular matrix proteome remodeling in Müller glial cells

Background The underlying pathomechanisms in diabetic retinopathy (DR) remain incompletely understood. The aim of this study was to add to the current knowledge about the particular role of retinal Müller glial cells (RMG) in the initial processes of DR. Methods Applying a quantitative proteomic workflow, we investigated changes of primary porcine RMG under short term high glucose treatment as well as glycolysis inhibition treatment. Results We revealed significant changes in RMG proteome primarily in proteins building the extracellular matrix (ECM) indicating fundamental remodeling processes of ECM as novel rapid response to high glucose treatment. Among others, Osteopontin (SPP1) as well as its interacting integrins were significantly downregulated and organotypic retinal explant culture confirmed the selective loss of SPP1 in RMG upon treatment. Since SPP1 in the retina has been described neuroprotective for photoreceptors and functions against experimentally induced cell swelling, it’s rapid loss under diabetic conditions may point to a direct involvement of RMG to the early neurodegenerative processes driving DR. Data are available via ProteomeXchange with identifier PXD015879.

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Neurons and Glia Interplay in α-Synucleinopathies

International Journal of Molecular Sciences ◽

10.3390/ijms22094994 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4994

Author(s):

Panagiota Mavroeidi ◽

Maria Xilouri

Keyword(s):

Glial Cells ◽

Current Knowledge ◽

Lewy Bodies ◽

Alpha Synuclein ◽

Lewy Neurites ◽

Cytoplasmic Inclusions ◽

Glial Cytoplasmic Inclusions ◽

Glial Function ◽

Presynaptic Protein

Accumulation of the neuronal presynaptic protein alpha-synuclein within proteinaceous inclusions represents the key histophathological hallmark of a spectrum of neurodegenerative disorders, referred to by the umbrella term a-synucleinopathies. Even though alpha-synuclein is expressed predominantly in neurons, pathological aggregates of the protein are also found in the glial cells of the brain. In Parkinson’s disease and dementia with Lewy bodies, alpha-synuclein accumulates mainly in neurons forming the Lewy bodies and Lewy neurites, whereas in multiple system atrophy, the protein aggregates mostly in the glial cytoplasmic inclusions within oligodendrocytes. In addition, astrogliosis and microgliosis are found in the synucleinopathy brains, whereas both astrocytes and microglia internalize alpha-synuclein and contribute to the spread of pathology. The mechanisms underlying the pathological accumulation of alpha-synuclein in glial cells that under physiological conditions express low to non-detectable levels of the protein are an area of intense research. Undoubtedly, the presence of aggregated alpha-synuclein can disrupt glial function in general and can contribute to neurodegeneration through numerous pathways. Herein, we summarize the current knowledge on the role of alpha-synuclein in both neurons and glia, highlighting the contribution of the neuron-glia connectome in the disease initiation and progression, which may represent potential therapeutic target for a-synucleinopathies.

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Hyperhomocysteinemia-induced death of retinal ganglion cells: The role of Müller glial cells and NRF2

Redox Biology ◽

10.1016/j.redox.2019.101199 ◽

2019 ◽

Vol 24 ◽

pp. 101199 ◽

Cited By ~ 13

Author(s):

Soumya Navneet ◽

Jing Zhao ◽

Jing Wang ◽

Barbara Mysona ◽

Shannon Barwick ◽

...

Keyword(s):

Retinal Ganglion Cells ◽

Glial Cells ◽

Ganglion Cells ◽

Retinal Ganglion ◽

Müller Glial Cells

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Potential role of glial cell line-derived neurotrophic factor receptors in Müller glial cells during light-induced retinal degeneration

Neuroscience ◽

10.1016/s0306-4522(03)00599-2 ◽

2003 ◽

Vol 122 (1) ◽

pp. 229-235 ◽

Cited By ~ 74

Author(s):

C Harada ◽

T Harada ◽

H.-M.A Quah ◽

F Maekawa ◽

K Yoshida ◽

...

Keyword(s):

Retinal Degeneration ◽

Cell Line ◽

Glial Cell ◽

Glial Cells ◽

Neurotrophic Factor ◽

Potential Role ◽

Müller Glial Cells

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The Role of Extracellular Matrix Molecules, Glial Cells, and Microglia in Regeneration of the Leech CNS

Neuron-Glia Interrelations During Phylogeny ◽

10.1385/0-89603-316-3:303 ◽

2003 ◽

pp. 303-324

Author(s):

Liria M. Masuda-Nakagawa

Keyword(s):

Extracellular Matrix ◽

Glial Cells ◽

Extracellular Matrix Molecules

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Regulatory role of eicosanoids in extracellular matrix overproduction induced by long-term exposure to high glucose in cultured rat mesangial cells

Diabetologia ◽

10.1007/s001250050553 ◽

1996 ◽

Vol 39 (9) ◽

pp. 1055-1062

Author(s):

F. Pricci ◽

G. Pugliese ◽

P. Men� ◽

G. Romeo ◽

G. Romano ◽

...

Keyword(s):

Extracellular Matrix ◽

High Glucose ◽

Mesangial Cells ◽

Regulatory Role

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Regulatory role of eicosanoids in extracellular matrix overproduction induced by long-term exposure to high glucose in cultured rat mesangial cells

Diabetologia ◽

10.1007/bf00400654 ◽

1996 ◽

Vol 39 (9) ◽

pp. 1055-1062 ◽

Cited By ~ 11

Author(s):

F. Pricci ◽

G. Pugliese ◽

P. Menè ◽

G. Romeo ◽

G. Romano ◽

...

Keyword(s):

Extracellular Matrix ◽

High Glucose ◽

Mesangial Cells ◽

Regulatory Role

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670nm photobiomodulation modulates bioenergetics and oxidative stress, in rat Müller cells challenged with high glucose

PLoS ONE ◽

10.1371/journal.pone.0260968 ◽

2021 ◽

Vol 16 (12) ◽

pp. e0260968

Author(s):

Hannah J. Nonarath ◽

Alexandria E. Hall ◽

Gopika SenthilKumar ◽

Betsy Abroe ◽

Janis T. Eells ◽

...

Keyword(s):

Oxidative Stress ◽

Glial Cells ◽

High Glucose ◽

Near Infrared ◽

Müller Cells ◽

Model System ◽

Light Treatment ◽

Muller Cells ◽

Müller Glial Cells

Diabetic retinopathy (DR), the most common complication of diabetes mellitus, is associated with oxidative stress, nuclear factor-κB (NFκB) activation, and excess production of vascular endothelial growth factor (VEGF) and intracellular adhesion molecule-1 (ICAM-1). Muller glial cells, spanning the entirety of the retina, are involved in DR inflammation. Mitigation of DR pathology currently occurs via invasive, frequently ineffective therapies which can cause adverse effects. The application of far-red to near-infrared (NIR) light (630-1000nm) reduces oxidative stress and inflammation in vitro and in vivo. Thus, we hypothesize that 670nm light treatment will diminish oxidative stress preventing downstream inflammatory mechanisms associated with DR initiated by Muller cells. In this study, we used an in vitro model system of rat Müller glial cells grown under normal (5 mM) or high (25 mM) glucose conditions and treated with a 670 nm light emitting diode array (LED) (4.5 J/cm2) or no light (sham) daily. We report that a single 670 nm light treatment diminished reactive oxygen species (ROS) production and preserved mitochondrial integrity in this in vitro model of early DR. Furthermore, treatment for 3 days in culture reduced NFκB activity to levels observed in normal glucose and prevented the subsequent increase in ICAM-1. The ability of 670nm light treatment to prevent early molecular changes in this in vitro high glucose model system suggests light treatment could mitigate early deleterious effects modulating inflammatory signaling and diminishing oxidative stress.

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Modulation of SOD3 Levels Is Detrimental to Retinal Homeostasis

Antioxidants ◽

10.3390/antiox10101595 ◽

2021 ◽

Vol 10 (10) ◽

pp. 1595

Author(s):

Larissa Ikelle ◽

Muna I. Naash ◽

Muayyad R. Al-Ubaidi

Keyword(s):

Oxidative Stress ◽

Extracellular Matrix ◽

Superoxide Dismutase ◽

Functional Decline ◽

Retinal Diseases ◽

Major Contributor ◽

Short Term ◽

Superoxide Dismutase 3 ◽

Secondary Feature

Retinal oxidative stress is a common secondary feature of many retinal diseases. Though it may not be the initial insult, it is a major contributor to the pathogenesis of highly prevalent retinal dystrophic diseases like macular degeneration, diabetic retinopathy, and retinitis pigmentosa. We explored the role of superoxide dismutase 3 (SOD3) in retinal homeostasis since SOD3 protects the extracellular matrix (ECM) from oxidative injury. We show that SOD3 is mainly extracellularly localized and is upregulated as a result of environmental and pathogenic stress. Ablation of SOD3 resulted in reduced functional electroretinographic responses and number of photoreceptors, which is exacerbated with age. By contrast, overexpression showed increased electroretinographic responses and increased number of photoreceptors at young ages, but appears deleterious as the animal ages, as determined from the associated functional decline. Our exploration shows that SOD3 is vital to retinal homeostasis but its levels are tightly regulated. This suggests that SOD3 augmentation to combat oxidative stress during retinal degenerative changes may only be effective in the short-term.

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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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