ON THE PATHOGENESIS OF DIABETIC RETINOPATHY, DAMAGE TO MULLER CELLS, DISEASES OF OPPONENTS, AND INFLAMMATION: A REVIEW

: 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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Angiopoietin-like 4 is a potent angiogenic factor and a novel therapeutic target for patients with proliferative diabetic retinopathy

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1423765112 ◽

2015 ◽

Vol 112 (23) ◽

pp. E3030-E3039 ◽

Cited By ~ 47

Author(s):

Savalan Babapoor-Farrokhran ◽

Kathleen Jee ◽

Brooks Puchner ◽

Syed Junaid Hassan ◽

Xiaoban Xin ◽

...

Keyword(s):

Diabetic Retinopathy ◽

Proliferative Diabetic Retinopathy ◽

Müller Cells ◽

Aqueous Fluid ◽

Angiogenic Factor ◽

Eye Disease ◽

Diabetic Patients ◽

Muller Cells ◽

Angiogenic Potential ◽

Diabetic Eye Disease

Diabetic eye disease is the most common cause of severe vision loss in the working-age population in the developed world, and proliferative diabetic retinopathy (PDR) is its most vision-threatening sequela. In PDR, retinal ischemia leads to the up-regulation of angiogenic factors that promote neovascularization. Therapies targeting vascular endothelial growth factor (VEGF) delay the development of neovascularization in some, but not all, diabetic patients, implicating additional factor(s) in PDR pathogenesis. Here we demonstrate that the angiogenic potential of aqueous fluid from PDR patients is independent of VEGF concentration, providing an opportunity to evaluate the contribution of other angiogenic factor(s) to PDR development. We identify angiopoietin-like 4 (ANGPTL4) as a potent angiogenic factor whose expression is up-regulated in hypoxic retinal Müller cells in vitro and the ischemic retina in vivo. Expression of ANGPTL4 was increased in the aqueous and vitreous of PDR patients, independent of VEGF levels, correlated with the presence of diabetic eye disease, and localized to areas of retinal neovascularization. Inhibition of ANGPTL4 expression reduced the angiogenic potential of hypoxic Müller cells; this effect was additive with inhibition of VEGF expression. An ANGPTL4 neutralizing antibody inhibited the angiogenic effect of aqueous fluid from PDR patients, including samples from patients with low VEGF levels or receiving anti-VEGF therapy. Collectively, our results suggest that targeting both ANGPTL4 and VEGF may be necessary for effective treatment or prevention of PDR and provide the foundation for studies evaluating aqueous ANGPTL4 as a biomarker to help guide individualized therapy for diabetic eye disease.

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Knockdown of KCNQ1OT1 Alleviates the Activation of NLRP3 Inflammasome Through miR-17-5p/TXNIP Axis in Retinal Müller Cells

10.21203/rs.3.rs-870214/v1 ◽

2021 ◽

Author(s):

Yu Liu ◽

Guoping Cao ◽

Lili Dong ◽

Lele Li ◽

Yuping Dou ◽

...

Keyword(s):

Diabetic Retinopathy ◽

Nlrp3 Inflammasome ◽

Critical Role ◽

Müller Cells ◽

Clinical Samples ◽

Inflammasome Activation ◽

Muller Cells ◽

Potential Mechanism ◽

Nlrp3 Inflammasome Activation ◽

Therapeutic Value

Abstract Diabetic retinopathy (DR) is one of the most severe and common complications caused by diabetic mellites. Inhibiting NLRP3 inflammasome activation displays a crucial therapeutic value in DR. Studies have shown that KCNQ1OT1 plays a critical role in regulating NLRP3 inflammasome activation and participates in the pathogenesis of diabetic complications. The present study aims to explore the role, and the potential mechanism of KCNQ1OT1 in regulating the activation of NLRP3 inflammasome in DR. The expression of KCNQ1OT1 and the activation of NLRP3 inflammasome were increased in experimental DR models. KCNQ1OT1 knockdown alleviated NLRP3 inflammasome-associated molecules expression. In addition, KCNQ1OT1 was found to be localized mainly in the cytoplasm of Müller cells and facilitated TXNIP expression by acting as a miR-17-5p sponge. KCNQ1OT1 promoted the activation of NLRP3 inflammasome through miR-17-5p/TXNIP axis. Moreover, the clinical samples of patients with DR showed that the expression of KCNQ1OT1 and the activation of NLRP3 inflammasome were all increased, further supporting the hypothesis that the KCNQ1OT1 dysregulation may be the molecular mechanism of the pathogenesis of DR. Therefore, KCNQ1OT1 may serve as a new therapeutic target for DR.

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Mediation of FoxO1 in Activated Neuroglia Deficient for Nucleoside Diphosphate Kinase B during Vascular Degeneration

Neuroglia ◽

10.3390/neuroglia1010019 ◽

2018 ◽

Vol 1 (1) ◽

pp. 280-291 ◽

Cited By ~ 1

Author(s):

Yi Qiu ◽

Hongpeng Huang ◽

Anupriya Chatterjee ◽

Loïc Teuma ◽

Fabienne Baumann ◽

...

Keyword(s):

Diabetic Retinopathy ◽

Cell Activation ◽

Neurovascular Unit ◽

Nucleoside Diphosphate Kinase ◽

Müller Cells ◽

Müller Cell ◽

Muller Cells ◽

Nucleoside Diphosphate Kinase B ◽

Muller Cell ◽

Underlying Mechanisms

The pathogenesis of diabetic retinopathy is closely associated with the breakdown of the neurovascular unit including the glial cells. Deficiency of nucleoside diphosphate kinase B (NDPK-B) results in retinal vasoregression mimicking diabetic retinopathy. Increased retinal expression of Angiopoietin-2 (Ang-2) initiates vasoregression. In this study, Müller cell activation, glial Ang-2 expression, and the underlying mechanisms were investigated in streptozotocin-induced diabetic NDPK-B deficient (KO) retinas and Müller cells isolated from the NDPK-B KO retinas. Müller cells were activated and Ang-2 expression was predominantly increased in Müller cells in normoglycemic NDPK-B KO retinas, similar to diabetic wild type (WT) retinas. Diabetes induction in the NDPK-B KO mice did not further increase its activation. Additionally, cultured NDPK-B KO Müller cells were more activated and showed higher Ang-2 expression than WT cells. Müller cell activation and Ang-2 elevation were observed upon high glucose treatment in WT, but not in NDPK-B KO cells. Moreover, increased levels of the transcription factor forkhead box protein O1 (FoxO1) were detected in non-diabetic NDPK-B KO Müller cells. The siRNA-mediated knockdown of FoxO1 in NDPK-B deficient cells interfered with Ang-2 upregulation. These data suggest that FoxO1 mediates Ang-2 upregulation induced by NDPK-B deficiency in the Müller cells and thus contributes to the onset of retinal vascular degeneration.

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

Oncotarget ◽

10.18632/oncotarget.13945 ◽

2016 ◽

Vol 8 (3) ◽

pp. 4582-4594 ◽

Cited By ~ 8

Author(s):

Ti Zhou ◽

Di Che ◽

Yuqing Lan ◽

Zhenzhen Fang ◽

Jinye Xie ◽

...

Keyword(s):

Diabetic Retinopathy ◽

Animal Models ◽

High Glucose ◽

Müller Cells ◽

Muller Cells ◽

Mesenchymal Marker ◽

Marker Expression

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CD40 in Retinal Müller Cells Induces P2X7-Dependent Cytokine Expression in Macrophages/Microglia in Diabetic Mice and Development of Early Experimental Diabetic Retinopathy

Diabetes ◽

10.2337/db16-0051 ◽

2016 ◽

Vol 66 (2) ◽

pp. 483-493 ◽

Cited By ~ 40

Author(s):

Jose-Andres C. Portillo ◽

Yalitza Lopez Corcino ◽

Yanling Miao ◽

Jie Tang ◽

Nader Sheibani ◽

...

Keyword(s):

Diabetic Retinopathy ◽

Müller Cells ◽

Cytokine Expression ◽

Muller Cells ◽

Diabetic Mice

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LncRNA XIST restrains the activation of Müller cells and inflammation in diabetic retinopathy via stabilizing SIRT1

Autoimmunity ◽

10.1080/08916934.2021.1969551 ◽

2021 ◽

pp. 1-10

Author(s):

Jiayu Zhang ◽

Chengwei Chen ◽

Sifang Zhang ◽

Jiawei Chen ◽

Liang Wu ◽

...

Keyword(s):

Diabetic Retinopathy ◽

Müller Cells ◽

Muller Cells ◽

Lncrna Xist

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Ranibizumab prevents Müller cell edema by decreasing VEGF-A in diabetic retinopathy

10.21203/rs.2.24500/v1 ◽

2020 ◽

Author(s):

Tianqin Wang ◽

Chaoyang Zhang ◽

Hai Xie ◽

Qiuxue Yi ◽

Dandan Liu ◽

...

Keyword(s):

Diabetic Retinopathy ◽

Potassium Level ◽

Müller Cells ◽

Müller Cell ◽

Intracellular Sodium ◽

K Channel ◽

Diabetic Rat ◽

Muller Cells ◽

Intracellular Potassium ◽

Muller Cell

Abstract Background: Diabetic macular edema (DME) is the most common cause of vision loss in patients with diabetic retinopathy. The efficacy of anti-VEGF therapy has been well demonstrated and become the standard of care in the management of DME. The present study is to explore the possible mechanism(s) of ranibizumab in protecting Müller cells from cellular edema in experimental diabetic retinopathy. Methods: Sprague-Dawley rats were rendered diabetes with intraperitoneal injection of streptozotocin. Intravitreal injection of ranibizumab was performed 8 weeks after diabetes onset. Four weeks later, the rats were killed and the retinas were harvested for examination. rMC-1 cells (rat Müller cell line) were treated with glyoxal for 24 hours, with or without ranibizumab. Cell viability was detected with CCK-8 assay. The expressions of inwardly rectifying K + channel 4.1 (Kir4.1), aquaporin 4 (AQP4), Dystrophin 71 (Dp71), vascular endothelial growth factor A (VEGF-A), glutamine synthetase (GS) and sodium-potassium-ATPase (Na + -K + -ATPase) were examined with Western blot. VEGF-A in the supernatant of cell culture was detected with ELISA. The intracellular potassium and sodium levels were detected with specific indicators. Results: Compared to the normal control, the protein expressions of Kir4.1, AQP4 and Dp71 were down-regulated significantly in diabetic rat retinas, which were prevented by ranibizumab. The above changes were recapitulated in vitro . As compared with the control, the intracellular potassium level in glyoxal-treated rMC-1 cells was increased, while the intracellular sodium level and Na + -K + -ATPase protein level remained unchanged. However, ranibizumab treatment increased Na + -K + -ATPase protein expression and decreased intracellular sodium, but not potassium level. Conclusion: Ranibizumab protected Müller cells from intracellular edema through up-regulation of Kir4.1, AQP4, and Dp71 by directly binding VEGF-A. It also increased the expression of Na + -K + -ATPase, contributing to reduction of the intracellular osmotic pressure.

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