Mesenchymal marker expression is elevated in Müller cells exposed to high glucose and in animal models of diabetic retinopathy

Background: The role of long non-coding RNA in diabetic retinopathy, a serious complication of diabetes mellitus, has attracted increasing attention in recent years. The purpose of this study was to explore whether long non-coding RNA nuclear paraspeckle assembly transcript 1 was involved in the context of diabetic retinopathy and its underlying mechanisms. Results: Our results revealed that nuclear paraspeckle assembly transcript 1 was significantly downregulated in the retina of diabetes mellitus rats. Meanwhile, miR-497 was significantly increased in diabetes mellitus rats’ retina and high glucose–treated Müller cells, but brain-derived neurotrophic factor was increased. We also found that high glucose–induced apoptosis of Müller cells was accompanied by the significant downregulation of nuclear paraspeckle assembly transcript 1 in vitro. Further study demonstrated that high glucose–promoted Müller cells apoptosis through downregulating nuclear paraspeckle assembly transcript 1 and downregulated nuclear paraspeckle assembly transcript 1 mediated this effect via negative regulating miR-497. Moreover, brain-derived neurotrophic factor was negatively regulated by miR-497 and associated with the apoptosis of Müller cells under high glucose. Conclusion: Our results suggested that under diabetic conditions, downregulated nuclear paraspeckle assembly transcript 1 decreased the expression of brain-derived neurotrophic factor through elevating miR-497, thereby promoting Müller cells apoptosis and aggravating diabetic retinopathy.

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TXNIP regulates mitophagy in retinal Müller cells under high-glucose conditions: implications for diabetic retinopathy

Cell Death and Disease ◽

10.1038/cddis.2017.190 ◽

2017 ◽

Vol 8 (5) ◽

pp. e2777-e2777 ◽

Cited By ~ 31

Author(s):

Takhellambam Swornalata Devi ◽

Mallika Somayajulu ◽

Renu Anjan Kowluru ◽

Lalit Pukhrambam Singh

Keyword(s):

Diabetic Retinopathy ◽

High Glucose ◽

Müller Cells ◽

Muller Cells

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Curcumin Attenuates Retinal Vascular Leakage by Inhibiting Calcium/Calmodulin-Dependent Protein Kinase II Activity in Streptozotocin-Induced Diabetes

Cellular Physiology and Biochemistry ◽

10.1159/000447826 ◽

2016 ◽

Vol 39 (3) ◽

pp. 1196-1208 ◽

Cited By ~ 19

Author(s):

Jun Li ◽

Peipei Wang ◽

Jia Ying ◽

Zhen Chen ◽

Songping Yu

Keyword(s):

Diabetic Retinopathy ◽

Protein Kinase ◽

Mechanism Of Action ◽

High Glucose ◽

Müller Cells ◽

Vascular Leakage ◽

Muller Cells ◽

Dependent Protein Kinase ◽

Calcium Calmodulin Dependent ◽

Dependent Protein

Background: Curcumin possesses many pharmacological properties including anti-inflammatory effects. Although prior studies indicate that curcumin has beneficial effects for diabetic retinopathy, the mechanism of action is not known. To address this issue, we investigated the effect of curcumin against diabetes-induced retinal vascular damage and its mechanism of action by using cultured retinal Müller cells stimulated with high glucose. Methods: We studied the effects of curcumin in vivo in the retinas of rats rendered diabetic by streptozotocin and in vitro in Müller cells stimulated with high glucose. We administered curcumin, or KN93, an inhibitor of calcium/calmodulin dependent protein kinase II (CaMKII), or saline vehicle to experimental animals on a daily basis for 12 weeks. Primary cultures of rat Müller cells were incubated with normal glucose or high glucose, with or without curcumin, KN93, or pyrrolidine dithiocarbamate (PDTC), an inhibitor of the transcription protein nuclear factor κB (NF-κB). We examined mRNA and protein levels of vascular endothelial growth factor (VEGF), inducible nitric oxide synthase (iNOS) and intercellular adhesion molecule-1 (ICAM-1) by real-time RT-PCR and Western blotting, respectively. Retinal levels of CaMKII and NF-κB were examined by Western blotting. Vascular leakage was evaluated using Evans blue. Results: Curcumin and KN93 significantly inhibited the activation of CaMKII/NF-κB signaling induced by diabetes or elevated glucose, and subsequently decreased the expression of VEGF, iNOS and ICAM-1. These changes were associated with a decrease of diabetes-induced retinal vascular leakage. Conclusion: Curcumin protects the diabetic rat retina against early retinal vascular damage, by inhibition of CaMKII activity. Curcumin is currently used to treat a number of clinical conditions, and may prove beneficial for the management of diabetic retinopathy.

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High-Glucose-Induced Rab20 Upregulation Disrupts Gap Junction Intercellular Communication and Promotes Apoptosis in Retinal Endothelial and Müller Cells: Implications for Diabetic Retinopathy

Journal of Clinical Medicine ◽

10.3390/jcm9113710 ◽

2020 ◽

Vol 9 (11) ◽

pp. 3710

Author(s):

Dongjoon Kim ◽

Casey Stottrup Lewis ◽

Vijay P. Sarthy ◽

Sayon Roy

Keyword(s):

Diabetic Retinopathy ◽

Gap Junction ◽

Intercellular Communication ◽

High Glucose ◽

Connexin 43 ◽

Müller Cells ◽

Muller Cells ◽

Dye Transfer ◽

Cx43 Expression ◽

Gap Junction Intercellular Communication

To investigate whether high glucose (HG) alters Rab20 expression and compromises gap junction intercellular communication (GJIC) and cell survival, retinal cells were studied for altered intracellular trafficking of connexin 43 (Cx43). Retinal endothelial cells (RRECs) and retinal Müller cells (rMCs) were grown in normal (N; 5 mM glucose) or HG (30 mM glucose) medium for seven days. In parallel, cells grown in HG medium were transfected with either Rab20 siRNA or scrambled siRNA as a control. Rab20 and Cx43 expression and their localization and distribution were assessed using Western Blot and immunostaining, respectively. Changes in GJIC activity were assessed using scrape load dye transfer, and apoptosis was identified using differential dye staining assay. In RRECs or rMCs grown in HG medium, Rab20 expression was significantly increased concomitant with a decreased number of Cx43 plaques. Importantly, a significant increase in the number of Cx43 plaques and GJIC activity was observed in cells transfected with Rab20 siRNA. Additionally, Rab20 downregulation inhibited HG-induced apoptosis in RRECs and rMCs. Results indicate HG-mediated Rab20 upregulation decreases Cx43 localization at the cell surface, resulting in compromised GJIC activity. Reducing Rab20 expression could be a useful strategy in preventing HG-induced vascular and Müller cell death associated with diabetic retinopathy.

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Activation of NFkB and Increased Pro‐Inflammatory ICAM‐1 in Retinal Glial (Müller) Cells in High Glucose, a Model of Diabetic Retinopathy, is Mediated via Upregulation of Glutaredoxin

The FASEB Journal ◽

10.1096/fasebj.21.6.a1036 ◽

2007 ◽

Vol 21 (6) ◽

Author(s):

Melissa DeAnn Shelton ◽

Timothy S Kern ◽

John J Mieyal

Keyword(s):

Diabetic Retinopathy ◽

High Glucose ◽

Müller Cells ◽

Muller Cells

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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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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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