High Glucose Alters Cx43 Expression and Gap Junction Intercellular Communication in Retinal Müller Cells: Promotes Müller Cell and Pericyte Apoptosis

Muto, Toshitaka; Tien, Thomas; Kim, Dongjoon; Sarthy, Vijay P.; Roy, Sayon

doi:10.1167/iovs.14-14606

Cited by 56 publications

(42 citation statements)

References 50 publications

(64 reference statements)

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“…100 glucoseeinduced changes in Cx43 expression in human DR, and the potential application of this knowledge in the treatment of DR, is only beginning to be understood. Our findings demonstrated that high glucoseeinduced Cx43 up-regulation may have protective effects on retinal Müller cells, 99 whereas a decreased level of Cx43 alone is sufficient to induce retinal vascular cell apoptosis. 100 Likewise, reduced levels of Cx43 are associated with retinal vascular lesions in human DR. 61 …”

Section: Connexinsmentioning

confidence: 66%

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Mechanistic Insights into Pathological Changes in the Diabetic Retina

Roy

Kern

Song

et al. 2017

The American Journal of Pathology

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166

147

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Increasing evidence points to inflammation as one of the key players in diabetes-mediating adverse effects to the neuronal and vascular components of the retina. Sustained inflammation induces biochemical and molecular changes, ultimately contributing to retinal complications and vision loss in diabetic retinopathy. In this review, we describe changes involving metabolic abnormalities secondary to hyperglycemia, oxidative stress, and activation of transcription factors, together with neuroglial alterations in the diabetic retina. Changes in biochemical pathways and how they promote pathophysiologic developments involving proinflammatory cytokines, chemokines, and adhesion molecules are discussed. Inflammation-mediated leukostasis, retinal ischemia, and neovascularization and their contribution to pathological and clinical stages leading to vision loss in diabetic retinopathy (DR) are highlighted. In addition, potential treatment strategies involving fibrates, connexins, neuroprotectants, photobiomodulation, and anti-inflammatory agents against the development and progression of DR lesions are reviewed. The importance of appropriate animal models for testing novel strategies against DR lesions is discussed; in particular, a novel nonhuman primate model of DR and the suitability of rodent models are weighed. The purpose of this review is to highlight our current understanding of the pathogenesis of DR and to summarize recent advances using novel approaches or targets to investigate and inhibit the retinopathy. (Am J Pathol 2017, 187: 9e19; http://dx

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Section: Connexinsmentioning

confidence: 66%

“…99,100 Down-regulation of Cx43 expression subsequently decreases cell-cell communication to promote vascular cell death and vascular permeability under high glucose conditions. 100 glucoseeinduced changes in Cx43 expression in human DR, and the potential application of this knowledge in the treatment of DR, is only beginning to be understood.…”

Section: Connexinsmentioning

confidence: 99%

Mechanistic Insights into Pathological Changes in the Diabetic Retina

Roy

Kern

Song

et al. 2017

The American Journal of Pathology

Self Cite

166

147

View full text Add to dashboard Cite

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“…Müller cell ablation leads to photoreceptor degeneration, vascular leak, and intraretinal neovascularization demonstrating that Müller cells are necessary for both neuronal and vascular function and viability[29,43]. Changes to their environment by hyperglycemia alters functional interaction with pericytes[44]. Deletion of the dystrophin-Dp71 protein within Müller cells caused extensive vascular leakage and edema in the mouse retina.…”

Section: Release Of Growth Factors and Pro-/anti-inflammatory Cytokinmentioning

confidence: 99%

Müller cells and diabetic retinopathy

2017

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Müller cells are one of the primary glial cell types found in the retina and play a significant role in maintaining retinal function and health. Since Müller cells are the only cell type to span the entire width of the retina and have contact to almost every cell type in the retina they are uniquely positioned to perform a wide variety of functions necessary to maintaining retinal homeostasis. In the healthy retina, Müller cells recycle neurotransmitters, prevent glutamate toxicity, redistribute ions by spatial buffering, participate in the retinoid cycle, and regulate nutrient supplies by multiple mechanisms. Any disturbance to the retinal environment is going to influence proper Müller cell function and well being which in turn will affect the entire retina. This is evident in a disease like diabetic retinopathy where Müller cells contribute to neuronal dysfunction, the production of pro-angiogenic factors leading to neovascularization, the set up of a chronic inflammatory retinal environment, and eventual cell death. In this review, we highlight the importance of Müller cells in maintaining a healthy and functioning retina and discuss various pathological events of diabetic retinopathy in which Müller cells seem to play a crucial role. The beneficial and detrimental effects of cytokine and growth factor production by Müller cells on the microvasculature and retinal neuronal tissue will be outlined. Understanding Müller cell functions within the retina and restoring such function in diabetic retinopathy should become a cornerstone for developing effective therapies to treat diabetic retinopathy.

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“…In addition, Cx43 is down-regulated in Müller glia in high glucose conditions, which leads to decreased gap junctions with pericytes and increased apoptosis in Müller glia and retinal microvascular endothelial cells (Li and Roy 2009; Muto et al 2014). Furthermore, retinas from diabetic or Cx43 heterozygous knockout mice develop retinal vascular lesions associated with diabetic retinopathies (Bobbie et al 2010).…”

Section: Xx3 Erp29 Connexin43 Trafficking and Gap Junctionsmentioning

confidence: 99%

Molecular Chaperone ERp29: A Potential Target for Cellular Protection in Retinal and Neurodegenerative Diseases

McLaughlin

Falkowski

Wang

et al. 2018

Retinal Degenerative Diseases

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The molecular chaperone endoplasmic reticulum protein 29 (ERp29) plays a critical role in protein folding, trafficking, and secretion. Though ubiquitously expressed, ERp29 is upregulated in response to ER stress and is found at higher levels in certain cell types such as secretory epithelial cells and neurons. As an ER resident protein, ERp29 shares many structural and functional similarities with protein disulfide-isomerases, but is not regarded as part of this family due to several key differences. The broad expression and myriad roles of ERp29 coupled with its upregulation via the unfolded protein response (UPR) upon ER stress has implicated ERp29 in a range of cellular process and diseases. We summarize the diverse activities of ERp29 in protein trafficking, cell survival and apoptosis, and ER homeostasis, and highlight a potential role of ERp29 in neuroprotection in retinal and neurodegenerative diseases.

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High Glucose Alters Cx43 Expression and Gap Junction Intercellular Communication in Retinal Müller Cells: Promotes Müller Cell and Pericyte Apoptosis

Cited by 56 publications

References 50 publications

Mechanistic Insights into Pathological Changes in the Diabetic Retina

Mechanistic Insights into Pathological Changes in the Diabetic Retina

Müller cells and diabetic retinopathy

Molecular Chaperone ERp29: A Potential Target for Cellular Protection in Retinal and Neurodegenerative Diseases

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