Suppression of protein kinase C-ζ attenuates vascular leakage via prevention of tight junction protein decrease in diabetic retinopathy

Song, Hyun Beom; Jun, Hyoung-Oh; Kim, Jin Hyoung; Yu, Young Suk; Kim, Kyu Won; Kim, Jeong Hun

doi:10.1016/j.bbrc.2014.01.002

Cited by 19 publications

(13 citation statements)

References 34 publications

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“…In addition, PKC-α, -γ, and -δ had an increased activity under hyperglycemic conditions, albeit to a lesser degree than PKC-β I and β II. Moreover, the inhibition of PKC-ζ decreased retinal vascular leakage by attenuating VEGF and AGE-induced decrease of tight junction proteins [115]. When clinical doses of VEGF were intravitreally injected, it resulted in rapid activation of PKC, and the membrane translocation of PKC-α, PKC-β, and PKC-δ leading to an increase in retinal vascular permeability [116].…”

Section: Molecular Mechanisms Of Diabetic Retinopathymentioning

confidence: 99%

Diabetic retinopathy: Breaking the barrier

et al. 2017

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Diabetic retinopathy (DR) remains a major complication of diabetes and a leading cause of blindness among adults worldwide. DR is a progressive disease affecting both type I and type II diabetic patients at any stage of the disease, and targets the retinal microvasculature. DR results from multiple biochemical, molecular and pathophysiological changes to the retinal vasculature, which affect both microcirculatory functions and ultimately photoreceptor function. Several neural, endothelial, and support cell (e.g., pericyte) mechanisms are altered in a pathological fashion in the hyperglycemic environment during diabetes that can disturb important cell surface components in the vasculature producing the features of progressive DR pathophysiology. These include loss of the glycocalyx, blood-retinal barrier dysfunction, increased expression of inflammatory cell markers and adhesion of blood leukocytes and platelets. Included in this review is a discussion of modifications that occur at or near the surface of the retinal vascular endothelial cells, and the consequences of these alterations on the integrity of the retina.

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Section: Molecular Mechanisms Of Diabetic Retinopathymentioning

confidence: 99%

Diabetic retinopathy: Breaking the barrier

et al. 2017

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“…PKC δ activation, related to its subcellular translocation and subsequent decrease of tight junction proteins ZO-1 and ZO-2, is involved in increased vascular permeability in AGE-treated RECs [41]. Further research proved that suppression of PKC ζ can also attenuates AGE-induced tight junction protein loss, therefore to prevent vascular leakage in diabetic retinopathy [38].…”

Section: Endothelial Dysfunctionmentioning

confidence: 99%

“…Adherens junctions (AJ) are mediated by VE-cadherin which promotes Ca 2+ -dependent homophilic cell to cell contacts, and interact intracellularly with actin cytoskeleton through catenins [36], while AGEs stimulation resulted in cleavage of VE-cadherin from the cell surface [39]. Treatments regarding to restore the expression of junction proteins are able to protect RECs from hyperglycemic insult to maintain their barrier properties [38,40]. Signaling events downstream of the AGE-RAGE pathway that dysregulate the junctional molecules were demonstrated in the last few years but still remained to be determined.…”

Section: Endothelial Dysfunctionmentioning

confidence: 99%

“…Phosphorylation and reorganization of the junction proteins is deemed as characteristic events in the development of barrier dysfunction [36]. Occludin, claudin-5 and zonula occludens (ZO) family are reported to be the principal tight junction (TJ) proteins found in retinal endothelial cells (RECs) [37,38]. Particularly, ZO-1 is a cytoplasmic protein that links occludin to the other intracellular junction structures [36].…”

Section: Endothelial Dysfunctionmentioning

confidence: 99%

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Involvement of Advanced Glycation End Products in the Pathogenesis of Diabetic Retinopathy

Chen

et al. 2018

Cell Physiol Biochem

157

106

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Diabetic retinopathy (DR) is a common and devastating microvascular complication of diabetes and a major cause of acquired blindness in young adults. Advanced glycation end products (AGEs) accumulated under hyperglycemic conditions are thought to play an important role in the pathogenesis of DR. AGEs can exert their deleterious effects by acting directly to induce aberrant crosslinking of extracellular matrix proteins, to increase vascular stiffness, altering vascular structure and function. Moreover, AGEs binding to the receptor for AGEs (RAGE) evokes intensive intracellular signaling cascades that leading to endothelial dysfunction, elaboration of key proinflammatory cytokines and proangiogenic factors, mediating pericyte apoptosis, vascular inflammation and angiogenesis, as well as breakdown of the inner blood-retinal barrier (BRB), the end result of all these events is damage to the neural and vascular components of the retina. Elucidation of AGE-induced mechanisms will help in the understanding of the complex cellular and molecular pathogenesis associated with DR. Novel anti-AGEs agents or AGE crosslink “breakers” are being investigated, it is hoped that in next few years, some of these promising therapies will be successfully applied in clinical context, aiming to reduce the major economical and medical burden caused by DR.

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“…In addition to PKCδ, work also suggests that PKCζ may be involved in retinal barrier changes in response to diabetes. Work in diabetic mice and RECs in high glucose demonstrated that inhibition of PKCζ could reduce VEGF-induced hyperpermeability (Song et al, 2014). Similar work by Titchenell et al (2012) also found that inhibition of atypical PKC (aPKC, PKCζ & ι/λ) prevented VEGF-induced barrier dysfunction.…”

Section: Introductionmentioning

confidence: 99%

Beta-adrenergic receptor agonist decreases VEGF levels through altered eNOS and PKC signaling in diabetic retina

2015

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Vascular endothelial cell growth factor (VEGF) is increased in diabetic macular edema. Compound 49b, a novel β-adrenergic receptor agonist, is protective in a type 1 diabetic rat model. We questioned whether Compound 49b could decrease VEGF levels, suggesting that Compound 49b may be effective against edema. Two-month diabetic rats received topical Compound 49b for 7 days only and/or insulin-like growth factor binding protein 3 (IGFBP-3) siRNA. We also measured endothelial nitric oxide synthase (eNOS) and protein kinase C (PKC)ζ and PKCδ phosphorylation. Retinal endothelial cells (RECs) cultured in high glucose were treated with Compound 49b and IGFBP-3 siRNA for evaluation of the same signaling pathways. Compound 49b significantly decreased VEGF through increased IGFBP-3 in the diabetic retina. Compound 49b also reduced eNOS, PKCζ and PKCδ phosphorylation in the diabetic retina and REC. Compound 49b regulated a number of proteins involved in REC barrier properties.

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Suppression of protein kinase C-ζ attenuates vascular leakage via prevention of tight junction protein decrease in diabetic retinopathy

Cited by 19 publications

References 34 publications

Diabetic retinopathy: Breaking the barrier

Diabetic retinopathy: Breaking the barrier

Involvement of Advanced Glycation End Products in the Pathogenesis of Diabetic Retinopathy

Beta-adrenergic receptor agonist decreases VEGF levels through altered eNOS and PKC signaling in diabetic retina

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