Muller cell changes in human diabetic retinopathy

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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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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Müller cell changes precede vascularization of the pigment epithelium in the dystrophic rat retina

Glia ◽

10.1002/glia.440030605 ◽

1990 ◽

Vol 3 (6) ◽

pp. 464-475 ◽

Cited By ~ 41

Author(s):

Rouel S. Roque ◽

Ruth B. Caldwell

Keyword(s):

Pigment Epithelium ◽

Müller Cell ◽

Rat Retina ◽

Muller Cell ◽

Cell Changes

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The role of Müller cell glucocorticoid signaling in diabetic retinopathy

Graefe s Archive for Clinical and Experimental Ophthalmology ◽

10.1007/s00417-019-04521-w ◽

2019 ◽

Vol 258 (2) ◽

pp. 221-230

Author(s):

Farhad Ghaseminejad ◽

Lew Kaplan ◽

Anna M. Pfaller ◽

Stefanie M. Hauck ◽

Antje Grosche

Keyword(s):

Diabetic Retinopathy ◽

Müller Cell ◽

Glucocorticoid Signaling ◽

Muller Cell

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IL-17A exacerbates diabetic retinopathy by impairing Müller cell function via Act1 signaling

Experimental & Molecular Medicine ◽

10.1038/emm.2016.117 ◽

2016 ◽

Vol 48 (12) ◽

pp. e280-e280 ◽

Cited By ~ 25

Author(s):

Ao-Wang Qiu ◽

Zheng Bian ◽

Ping-An Mao ◽

Qing-Huai Liu

Keyword(s):

Diabetic Retinopathy ◽

Cell Function ◽

Müller Cell ◽

Muller Cell

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Proteomic phenotyping of stimulated Müller cells uncovers profound pro-inflammatory signaling and antigen-presenting capacity

10.1101/2021.08.29.458112 ◽

2021 ◽

Author(s):

Adrian Schmalen ◽

Lea Lorenz ◽

Antje Grosche ◽

Diana Pauly ◽

Cornelia A. Deeg ◽

...

Keyword(s):

Diabetic Retinopathy ◽

Mhc Class Ii ◽

Müller Cells ◽

Active Role ◽

Müller Cell ◽

Muller Cells ◽

Inflammatory Phenotype ◽

Retinal Inflammation ◽

Muller Cell ◽

Antigen Presenting

AbstractMüller cells are the main macroglial cells of the retina exerting a wealth of functions to maintain retinal homoeostasis. Upon pathological changes in the retina, they become gliotic with both protective and detrimental consequences. Accumulating data also provide evidence for a pivotal role of Müller cells in the pathogenesis of diabetic retinopathy (DR). While microglial cells, the resident immune cells of the retina are considered as main players in inflammatory processes associated with DR, the implication of activated Müller cells in chronic retinal inflammation remains to be elucidated. In order to assess the signaling capacity of Müller cells and their role in retinal inflammation, we performed in-depth proteomic analysis of Müller cell proteomes and secretomes after stimulation with INFγ, TNFα, IL-4, IL-6, IL-10, VEGF, TGFβ1, TGFβ2 and TGFβ3. We used both, primary porcine Müller cells and the human Müller cell line MIO-M1 for our hypothesis generating approach. Our results point towards an intense signaling capacity of Müller cells, which reacted in a highly discriminating manner upon treatment with different cytokines. Stimulation of Müller cells resulted in a primarily pro-inflammatory phenotype with secretion of cytokines and components of the complement system. Furthermore, we observed evidence for mitochondrial dysfunction, implying oxidative stress after treatment with the various cytokines. Finally, both MIO-M1 cells and primary porcine Müller cells showed several characteristics of atypical antigen-presenting cells, as they are capable of inducing MHC class I and MHC class II with co-stimulatory molecules. In line with this, they express proteins associated with formation and maturation of phagosomes. Thus, our findings underline the importance of Müller cell signaling in the inflamed retina, indicating an active role in chronic retinal inflammation underlying the pathogenesis of diabetic retinopathy.

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