Tumor Necrosis Factor Alpha (TNF-α) Disrupts Kir4.1 Channel Expression Resulting in Müller Cell Dysfunction in the Retina

Hassan, Iraj; Luo, Qianyi; Majumdar, Sreeparna; Dominguez, James M.; Busik, Julia V.; Bhatwadekar, Ashay D.

doi:10.1167/iovs.16-20712

Cited by 18 publications

(20 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The gliosis of Müller cells is associated with a functional uncoupling from neurons, which contributes to neurodegeneration and impedes tissue repair and regular neuroregeneration. Gliotic Müller cells have direct cytotoxic effects mediated by the release of soluble proinflammatory cytokines including TNFα ( Hassan et al, 2017 ), IL-1β ( Yego et al, 2009 ), ICAM-1 ( Wang et al, 2010 ), and MCP-1 ( Eastlake et al, 2016 ). In primary cultured retinal Müller cells, LPS (1000 ng/ml) stimulation significantly upregulated the expression of GFAP, TNFα, IL-1β, ICAM-1, and MCP-1 and downregulated the functional protein AQP4.…”

Section: Discussionmentioning

confidence: 99%

A Synthesized Glucocorticoid- Induced Leucine Zipper Peptide Inhibits Retinal Müller Cell Gliosis

Ding

Tang

et al. 2018

Front. Pharmacol.

View full text Add to dashboard Cite

Purpose: The anti-inflammatory activities of protein glucocorticoid-induced leucine zipper (GILZ) have been demonstrated in vivo and in vitro. Here, we examined the potential effect of a synthetic peptide derived from the leucine zipper motif and proline-rich region of GILZ on suppressing inflammatory responses in primary cultured rat Müller cells.Methods: Peptides were selected from amino acids 98–134 of the GILZ protein (GILZ-p). Solid-phase peptide synthesis was used to generate the cell-penetrating peptide TAT, which was bound to the amino terminus of GILZ-p. Primary cultured retinal Müller cells were stimulated with lipopolysaccharide (LPS) alone or in combination with different concentrations of GILZ-p, and the interaction of GILZ-p with nuclear factor (NF)-κB p65 in Müller cells was investigated by western blotting, immunoprecipitation, and immunofluorescence. The expression of the Müller cell gliosis marker glial fibrillary acidic protein (GFAP), functional protein aquaporin (AQP)-4, and the inflammatory cytokines interleukin (IL)-1β, tumor necrosis factor (TNF) α, intercellular adhesion molecule (ICAM)-1, and monocyte chemoattractant protein (MCP)-1 was measured by Western Blotting. The concentration of those cytokines in culture medium was measured by using Enzyme-Linked Immunosorbent Assay.Results: The synthesized GILZ-p, which was water-soluble, entered cells and bound with NF-κB p65, inhibiting p65 nuclear translocation. GILZ-p inhibited the LPS-induced expression of GFAP, IL-1β, TNFα, ICAM-1, and MCP-1 in Müller cells and prevented the LPS-induced downregulation of AQP4.Conclusions: These results indicate that GILZ-p interacted with NF-κB p65 and suppressed p65 nuclear translocation, thereby inhibiting inflammatory cytokine release and Müller cell gliosis.

show abstract

Section: Discussionmentioning

confidence: 99%

A Synthesized Glucocorticoid- Induced Leucine Zipper Peptide Inhibits Retinal Müller Cell Gliosis

Ding

Tang

et al. 2018

Front. Pharmacol.

View full text Add to dashboard Cite

show abstract

“…Briefly, several authors have also reported strong negative correlations between the extent of membrane lipid peroxidation and NKA activity in vivo in illnesses as diverse as cardiovascular disease, SZ, and BPD [255,256,261]. The relationship between increased membrane lipid peroxidation and increasing NKA dysfunction appears to be mediated by decreased membrane fluidity and PUFA content [260,262]. This is of importance as several studies have reported a significant increase in NKA activity following dietary supplementation with PUFAs [260,[263][264][265].…”

Section: Nutritional Ketosis Astrogliosis and Nka Functionmentioning

confidence: 97%

“…The causative role played by oxidative and nitrosative stress in NKA downregulation is further emphasized by studies reporting that prolonged use of antioxidant combinations such as vitamin C and E or N-acetylcysteine, α-tocopherol, and α-lipoic acid can produce clinically significant increases in NKA activity in the brain and periphery [259,260]. Thus, there is a prospect that the welldocumented antioxidant properties of the KD may exert a similar effect assuming a similar effect size and may well underpin the observations reporting a positive effect of the KD on improving NKA function discussed above.…”

Section: Nutritional Ketosis Astrogliosis and Nka Functionmentioning

confidence: 99%

“…The relationship between increased membrane lipid peroxidation and increasing NKA dysfunction appears to be mediated by decreased membrane fluidity and PUFA content [260,262]. This is of importance as several studies have reported a significant increase in NKA activity following dietary supplementation with PUFAs [260,[263][264][265]. These observations may be explained by reference to data confirming that dietary PUFAs can integrate into lipid membranes in the periphery and the brain combatting the drivers of lipid peroxidation and increasing membrane fluidity via mechanism (reviewed by [266]).…”

Section: Nutritional Ketosis Astrogliosis and Nka Functionmentioning

confidence: 99%

See 1 more Smart Citation

Nutritional ketosis as an intervention to relieve astrogliosis: Possible therapeutic applications in the treatment of neurodegenerative and neuroprogressive disorders

et al. 2020

View full text Add to dashboard Cite

Nutritional ketosis, induced via either the classical ketogenic diet or the use of emulsified medium-chain triglycerides, is an established treatment for pharmaceutical resistant epilepsy in children and more recently in adults. In addition, the use of oral ketogenic compounds, fractionated coconut oil, very low carbohydrate intake, or ketone monoester supplementation has been reported to be potentially helpful in mild cognitive impairment, Parkinson’s disease, schizophrenia, bipolar disorder, and autistic spectrum disorder. In these and other neurodegenerative and neuroprogressive disorders, there are detrimental effects of oxidative stress, mitochondrial dysfunction, and neuroinflammation on neuronal function. However, they also adversely impact on neurone–glia interactions, disrupting the role of microglia and astrocytes in central nervous system (CNS) homeostasis. Astrocytes are the main site of CNS fatty acid oxidation; the resulting ketone bodies constitute an important source of oxidative fuel for neurones in an environment of glucose restriction. Importantly, the lactate shuttle between astrocytes and neurones is dependent on glycogenolysis and glycolysis, resulting from the fact that the astrocytic filopodia responsible for lactate release are too narrow to accommodate mitochondria. The entry into the CNS of ketone bodies and fatty acids, as a result of nutritional ketosis, has effects on the astrocytic glutamate–glutamine cycle, glutamate synthase activity, and on the function of vesicular glutamate transporters, EAAT, Na+, K+-ATPase, Kir4.1, aquaporin-4, Cx34 and KATP channels, as well as on astrogliosis. These mechanisms are detailed and it is suggested that they would tend to mitigate the changes seen in many neurodegenerative and neuroprogressive disorders. Hence, it is hypothesized that nutritional ketosis may have therapeutic applications in such disorders.

show abstract

“…Notably, the polarized pattern of Kir4.1 exhibits a strong decrease in perivascular regions in diabetic retinas expressing Müller cell markers [ 11 , 12 ]. Our studies demonstrate that Müller cells exhibit a functional clock with a diurnal rhythm of Kir4.1 and diabetes disturbs the natural circadian rhythm of Kir4.1 [ 13 ]. AGEs are known to induce Müller cell dysfunction [ 14 ], but it remains unknown how AGE-modification of BM affects Kir4.1 channels in diabetes.…”

Section: Introductionmentioning

confidence: 99%

Advanced glycation end (AGE) product modification of laminin downregulates Kir4.1 in retinal Müller cells

et al. 2018

Self Cite

View full text Add to dashboard Cite

Diabetic retinopathy (DR) is a major cause of adult blindness. Retinal Müller cells maintain water homeostasis and potassium concentration via inwardly rectifying Kir4.1 channels. Accumulation of advanced glycation end products (AGEs) is a major pathologic event in DR. While diabetes leads to a decrease in the Kir4.1 channels, it remains unknown whether AGEs-linked to the basement membrane (BM) affect normal Kir4.1 channels. For this study, we hypothesized that AGE-modification of laminin is detrimental to Kir4.1 channels, therefore, disrupting Müller cell function. The AGE-modified laminin-coated substrates were prepared by incubating Petri-dishes with laminin and methylglyoxal for seven days. The rat Müller cells (rMC-1) were propagated on AGE-modified laminin, and Kir4.1 expression and function were evaluated. Quantification of AGEs using ELISA revealed a dose-dependent increase in methylglyoxal-hydro-imidazolone adducts. The rMC-1 propagated on AGE-modified laminin demonstrated a decrease in Kir4.1 levels in immunofluorescence and western blot studies and a decrease in the Kir4.1 channel function. Kir4.1 decrease on AGE-modified laminin resulted in a disorganization of an actin cytoskeleton and disruption of α-dystroglycan-syntrophin-dystrophin complexes. Our studies suggest that AGE-modification of laminin is detrimental to Kir4.1 channels. By studying the role of AGEs in Kir4.1 channels we have identified a novel mechanism of Müller cell dysfunction and its subsequent involvement in DR.

show abstract

Tumor Necrosis Factor Alpha (TNF-α) Disrupts Kir4.1 Channel Expression Resulting in Müller Cell Dysfunction in the Retina

Abstract: Our findings demonstrate that Kir4.1 channels possess a diurnal rhythm, and this rhythm is dampened with diabetes, thereby suggesting that the increase in TNF-α is detrimental to normal Kir4.1 rhythm and expression.

Cited by 18 publications

References 36 publications

A Synthesized Glucocorticoid- Induced Leucine Zipper Peptide Inhibits Retinal Müller Cell Gliosis

A Synthesized Glucocorticoid- Induced Leucine Zipper Peptide Inhibits Retinal Müller Cell Gliosis

Nutritional ketosis as an intervention to relieve astrogliosis: Possible therapeutic applications in the treatment of neurodegenerative and neuroprogressive disorders

Advanced glycation end (AGE) product modification of laminin downregulates Kir4.1 in retinal Müller cells

Contact Info

Product

Resources

About