scholarly journals Blocking IL-17A Alleviates Diabetic Retinopathy in Rodents

2017 ◽  
Vol 41 (3) ◽  
pp. 960-972 ◽  
Author(s):  
Ao-Wang Qiu ◽  
Qing-Huai Liu ◽  
Jun-Ling Wang
Keyword(s):  
Diabetic Retinopathy ◽  
Intravitreal Injection ◽  
Cell Function ◽  
Autoimmune Diabetes ◽  
Müller Cell ◽  
Cell Dysfunction ◽  
Junction Protein ◽  
Neutralizing Monoclonal Antibody ◽  
Muller Cell

Background/Aims: Interleukin (IL)-17A, a proinflammatory cytokine, has been implicated in several autoimmune diseases. However, it is unclear whether IL-17A is involved in diabetic retinopathy (DR), one of the most serious complications of autoimmune diabetes. This study aimed to demonstrate that IL-17A exacerbates DR by affecting retinal Müller cell function. Methods: High glucose (HG)-treated rat Müller cell line (rMC-1) was exposed to IL-17A, anti-IL-17A-neutralizing monoclonal antibody (mAb) or/and anti-IL-17 receptor (R)A-neutralizing mAb for 24 h. For in vivo study, DR was induced by intraperitoneal injections of streptozotocin (STZ). DR model mice were treated with anti-IL-17A mAb or anti-IL-17RA mAb in the vitreous cavity. Mice that were prepared for retinal angiography were sacrificed two weeks after intravitreal injection, while the rest were sacrificed two days after intravitreal injection. Results: IL-17A production and IL-17RA expression were increased in both HG-treated rMC-1 and DR retina. HG induced rMC-1 activation and dysfunction, as determined by the increased GFAP, VEGF and glutamate levels as well as the downregulated GS and EAAT1 expression. IL-17A exacerbated the HG-induced rMC-1 functional disorders, whereas either anti-IL-17A mAb or anti-IL-17RA mAb alleviated the HG-induced rMC-1 disorders. Intravitreal injections with anti-IL-17A mAb or anti-IL-17RA mAb in DR model mice reduced Müller cell dysfunction, vascular leukostasis, vascular leakage, tight junction protein downregulation and ganglion cell apoptosis in the retina. Conclusions: IL-17A aggravates DR-like pathology at least partly by impairing retinal Müller cell function. Blocking IL-17A is a potential therapeutic strategy for DR.

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

2016 ◽  
Vol 48 (12) ◽  
pp. e280-e280 ◽  
Author(s):  
Ao-Wang Qiu ◽  
Zheng Bian ◽  
Ping-An Mao ◽  
Qing-Huai Liu
Keyword(s):  
Diabetic Retinopathy ◽  
Cell Function ◽  
Müller Cell ◽  
Muller Cell

Temporary impairment of Müller cell metabolism in the rat retina by intravitreal injection of fluorocitrate

1991 ◽  
Vol 53 (1) ◽  
pp. 115-122 ◽  
Author(s):  
M. Virgili ◽  
R. Paulsen ◽  
L. Villani ◽  
A. Contestabile ◽  
F. Fonnum
Keyword(s):  
Intravitreal Injection ◽  
Cell Metabolism ◽  
Müller Cell ◽  
Rat Retina ◽  
Muller Cell

Müller cell gliosis in retinal organ culture mimics gliotic alterations after ischemia in vivo

2008 ◽  
Vol 26 (7) ◽  
pp. 745-751 ◽  
Author(s):  
Heidrun Kuhrt ◽  
Antje Wurm ◽  
Anett Karl ◽  
Ianors Iandiev ◽  
Peter Wiedemann ◽  
...  
Keyword(s):  
Organ Culture ◽  
Müller Cell ◽  
Muller Cell

scholarly journals α-Cell Dysfunctions and Molecular Alterations in Male Insulinopenic Diabetic Mice Are Not Completely Corrected by Insulin

Endocrinology ◽  
2015 ◽  
Vol 157 (2) ◽  
pp. 536-547 ◽  
Author(s):  
Rodolphe Dusaulcy ◽  
Sandra Handgraaf ◽  
Mounia Heddad-Masson ◽  
Florian Visentin ◽  
Christian Vesin ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Insulin Treatment ◽  
Cell Function ◽  
Cell Mass ◽  
Glucagon Secretion ◽  
Diabetic Mice ◽  
Differentiation Markers ◽  
Molecular Alteration ◽  
Cell Dysfunction

Abstract Glucagon and α-cell dysfunction are critical in the development of hyperglycemia during diabetes both in humans and rodents. We hypothesized that α-cell dysfunction leading to dysregulated glucagon secretion in diabetes is due to both a lack of insulin and intrinsic defects. To characterize α-cell dysfunction in diabetes, we used glucagon-Venus transgenic male mice and induced insulinopenic hyperglycemia by streptozotocin administration leading to alterations of glucagon secretion. We investigated the in vivo impact of insulinopenic hyperglycemia on glucagon-producing cells using FACS-sorted α-cells from control and diabetic mice. We demonstrate that increased glucagonemia in diabetic mice is mainly due to increases of glucagon release and biosynthesis per cell compared with controls without changes in α-cell mass. We identified genes coding for proteins involved in glucagon biosynthesis and secretion, α-cell differentiation, and potential stress markers such as the glucagon, Arx, MafB, cMaf, Brain4, Foxa1, Foxa3, HNF4α, TCF7L2, Glut1, Sglt2, Cav2.1, Cav2.2, Nav1.7, Kir6.2/Sur1, Pten, IR, NeuroD1, GPR40, and Sumo1 genes, which were abnormally regulated in diabetic mice. Importantly, insulin treatment partially corrected α-cell function and expression of genes coding for proglucagon, or involved in glucagon secretion, glucose transport and insulin signaling but not those coding for cMAF, FOXA1, and α-cell differentiation markers as well as GPR40, NEUROD1, CAV2.1, and SUMO1. Our results indicate that insulinopenic diabetes induce marked α-cell dysfunction and molecular alteration, which are only partially corrected by in vivo insulin treatment.

Muller cell changes in human diabetic retinopathy

Diabetes ◽  
1998 ◽  
Vol 47 (3) ◽  
pp. 445-449 ◽  
Author(s):  
M. Mizutani ◽  
C. Gerhardinger ◽  
M. Lorenzi
Keyword(s):  
Diabetic Retinopathy ◽  
Müller Cell ◽  
Muller Cell ◽  
Cell Changes

scholarly journals Yap haploinsufficiency leads to Müller cell dysfunction and late-onset cone dystrophy

2020 ◽  
Author(s):  
Christel Masson ◽  
Diana Garcia-Garcia ◽  
Juliette Bitard ◽  
Elodie Grellier ◽  
Jerome E Roger ◽  
...  
Keyword(s):  
Late Onset ◽  
Müller Cell ◽  
Cone Dystrophy ◽  
Visual Response ◽  
Muller Glia ◽  
Müller Glia ◽  
Cell Dysfunction ◽  
Gene Compensation ◽  
Muller Cell ◽  
Cone Opsins

Hippo signalling regulates eye growth during embryogenesis through its effectors YAP and TAZ. Taking advantage of a Yap heterozygous mouse line, we here sought to examine its function in adult neural retina, where YAP expression is restricted to Müller glia. We first discovered an unexpected temporal dynamic of gene compensation. At post-natal stages, Taz upregulation occurs, leading to a gain of function-like phenotype characterized by EGFR signalling potentiation and delayed cell cycle exit of retinal progenitors. In contrast, Yap+/- adult retinas no longer exhibit TAZ-dependent dosage compensation. In this context, Yap haploinsufficiency in aged individuals results in Müller glia dysfunction, late-onset cone degeneration and reduced cone-mediated visual response. Alteration of glial homeostasis and altered patterns of cone opsins were also observed in Müller cell specific conditional Yap knockout mice. Together, this study highlights a novel YAP function in Müller cells for the maintenance of retinal tissue homeostasis and the preservation of cone integrity. It also suggests that YAP haploinsufficiency should be considered and explored as a cause of cone dystrophies in human.

scholarly journals Retinal Inflammation, Oxidative Stress, and Vascular Impairment Is Ablated in Diabetic Mice Receiving XMD8-92 Treatment

2021 ◽  
Vol 12 ◽  
Author(s):  
Scott J. Howell ◽  
Chieh A. Lee ◽  
Julia C. Batoki ◽  
Thomas E. Zapadka ◽  
Sarah I. Lindstrom ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetic Retinopathy ◽  
New Drugs ◽  
Type I ◽  
Type Ii ◽  
Diabetic Mice ◽  
Junction Protein ◽  
Type Ii Diabetics ◽  
Retinal Inflammation

The global number of diabetics continues to rise annually. As diabetes progresses, almost all of Type I and more than half of Type II diabetics develop diabetic retinopathy. Diabetic retinopathy is a microvascular disease of the retina, and is the leading cause of blindness in the working-age population worldwide. With such a significant health impact, new drugs are required to halt the blinding threat posed by this visual disorder. The cause of diabetic retinopathy is multifactorial, and an optimal therapeutic would halt inflammation, cease photoreceptor cell dysfunction, and ablate vascular impairment. XMD8-92 is a small molecule inhibitor that blocks inflammatory activity downstream of ERK5 (extracellular signal-related kinase 5) and BRD4 (bromodomain 4). ERK5 elicits inflammation, is increased in Type II diabetics, and plays a pathologic role in diabetic nephropathy, while BRD4 induces retinal inflammation and plays a role in retinal degeneration. Further, we provide evidence that suggests both pERK5 and BRD4 expression are increased in the retinas of our STZ (streptozotocin)-induced diabetic mice. Taken together, we hypothesized that XMD8-92 would be a good therapeutic candidate for diabetic retinopathy, and tested XMD8-92 in a murine model of diabetic retinopathy. In the current study, we developed an in vivo treatment regimen by administering one 100 μL subcutaneous injection of saline containing 20 μM of XMD8-92 weekly, to STZ-induced diabetic mice. XMD8-92 treatments significantly decreased diabetes-mediated retinal inflammation, VEGF production, and oxidative stress. Further, XMD8-92 halted the degradation of ZO-1 (zonula occludens-1), which is a tight junction protein associated with vascular permeability in the retina. Finally, XMD8-92 treatment ablated diabetes-mediated vascular leakage and capillary degeneration, which are the clinical hallmarks of non-proliferative diabetic retinopathy. Taken together, this study provides strong evidence that XMD8-92 could be a potentially novel therapeutic for diabetic retinopathy.

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

Neuroglia ◽  
2018 ◽  
Vol 1 (1) ◽  
pp. 280-291 ◽  
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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