An Update on Connexin Gap Junction and Hemichannels in Diabetic Retinopathy

González-Casanova, Jorge Enrique; Schmachtenberg, Oliver; Martı́nez, Agustı́n D.; Sánchez, Helmuth A.; Harcha, Paloma A.; Rojas-Gómez, Diana Marcela

doi:10.3390/ijms22063194

Cited by 14 publications

(14 citation statements)

References 186 publications

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“…Moreover, a recent study by Lyon et al identified that inflammation coupled with glycaemic damage mediates EMT of the RPE via aberrant Cx43 mediated hemichannel activity [ 50 ], whilst Peptide 5 blocked loss of ZO-1 expression and restores RPE permeability as measured by transepithelial resistance [ 125 ]. These studies further support the extensive work in the field of connexin biology and ophthalmology, which in recent years has identified a key pathological role for connexin hemichannels in ophthalmological disease [ 47 ].…”

Section: The Therapeutic Potential Of Blocking Cx43 In Diabetic Retinopathysupporting

confidence: 72%

“…Dysregulation of hemichannel function is associated with chronic diseases, including deafness [ 39 ], brain ischaemia [ 40 ] and chronic pain [ 41 , 42 ]. The role of hyperglycaemia in regulating connexin expression [ 43 , 44 ], gap junction communication [ 45 ] and hemichannel activity [ 46 , 47 , 48 ] is well documented [ 49 ], and of the 21 isoforms known to be expressed within the human body, Cx43 has been strongly linked to the pathogenesis of multiple secondary complications of diabetes [ 43 , 50 , 51 , 52 ]. In this article, we review a role for Cx43 hemichannels in chronic inflammation and microvascular complications of diabetic nephropathy and retinopathy, ahead of exploring the therapeutic potential of hemichannel blockers in preventing disease progression.…”

Section: Introductionmentioning

confidence: 99%

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Connexin 43: A Target for the Treatment of Inflammation in Secondary Complications of the Kidney and Eye in Diabetes

Cliff

Williams

Chadjichristos

et al. 2022

IJMS

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Of increasing prevalence, diabetes is characterised by elevated blood glucose and chronic inflammation that precedes the onset of multiple secondary complications, including those of the kidney and the eye. As the leading cause of end stage renal disease and blindness in the working population, more than ever is there a demand to develop clinical interventions which can both delay and prevent disease progression. Connexins are membrane bound proteins that can form pores (hemichannels) in the cell membrane. Gated by cellular stress and injury, they open under pathophysiological conditions and in doing so release ‘danger signals’ including adenosine triphosphate into the extracellular environment. Linked to sterile inflammation via activation of the nod-like receptor protein 3 inflammasome, targeting aberrant hemichannel activity and the release of these danger signals has met with favourable outcomes in multiple models of disease, including secondary complications of diabetes. In this review, we provide a comprehensive update on those studies which document a role for aberrant connexin hemichannel activity in the pathogenesis of both diabetic eye and kidney disease, ahead of evaluating the efficacy of blocking connexin-43 specific hemichannels in these target tissues on tissue health and function.

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Section: The Therapeutic Potential Of Blocking Cx43 In Diabetic Retinopathysupporting

confidence: 72%

Section: Introductionmentioning

confidence: 99%

Connexin 43: A Target for the Treatment of Inflammation in Secondary Complications of the Kidney and Eye in Diabetes

Cliff

Williams

Chadjichristos

et al. 2022

IJMS

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“…Intriguingly, we found that Cx43 was distributed between c-kit + cells and SCF-expressing Müller cells, suggesting physical connection between these cells may exist. In the retina, Cx43 is expressed within the perivascular endfeet of astrocytes, Müller cells, retinal pigment epithelium and some neurons, and has been functionally associated with vascular regulation ( Gonzalez-Casanova et al, 2021 ). The regulatory role of Cx43 in the endogenous SCF/c-kit signaling pathway has not been fully explored.…”

Section: Discussionmentioning

confidence: 99%

Stimulation of C-Kit+ Retinal Progenitor Cells by Stem Cell Factor Confers Protection Against Retinal Degeneration

Chen

Liu

et al. 2022

Front. Pharmacol.

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C-kit/CD117, expressed in a series of tissue-specific progenitor cells, plays an important role in tissue regeneration and tissue homeostasis. We previously demonstrated that organoid-derived c-kit+ retinal progenitor cells can facilitate the restoration of degenerated retina. Meanwhile, we have identified a population of endogenous c-kit+ cells in retinas of adult mouse. However, the exact role of these cells in retinal degeneration remains unclear. Here, we demonstrated that stimulation of endogenous c-kit+ cells by stem cell factor (SCF) conferred protection against retinal degeneration. Retinal degeneration was induced by intravitreal injection of N-methyl-D-aspartate (NMDA). NMDA challenge increased the total number of c-kit+ cells in the retinal ganglion cell layer (GCL), while deregulated the protein level of SCF, which was mainly expressed in Müller cells. Both flash electroretinogram (fERG) and light/dark transition tests showed that intravitreal injection of SCF effectively improved the visual function of NMDA-treated mice. Mechanistically, SCF administration not only prevented the loss of retinal ganglion cells (RGCs), but also maintained the function of RGCs as quantified by fERG. Further, we performed transcriptome sequencing analysis of the retinal cells isolated from SCF-treated mice and the parallel control. Gene Ontology analysis showed that SCF-induced transcriptome changes were closely correlated with eye development-related pathways. Crystallins and several protective factors such as Pitx3 were significantly upregulated by SCF treatment. Our results revealed the role of SCF stimulated c-kit+ cells in the protection of RGCs in NMDA-treated mice, via inhibiting the loss of RGCs. Administration of SCF can act as a potent strategy for treating retinal degeneration-related diseases.

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“…Since Cx HCs form poorly selective ion channels of high conductance, their opening leads to an influx of Ca 2+ , breakdown of the electrochemical gradient across the plasma membrane, and loss of essential metabolites. HCs are activated under pathological conditions, including oxidative stress, mechanical stretch, inflammatory processes, and low pH [61][62][63][64][65][66][67]. An exacerbated HC activity during pathological states can increase cell damage.…”

Section: Connexin Forms Gap Junction Channels and Hemichannelsmentioning

confidence: 99%

New Insights on the Role of Connexins and Gap Junctions Channels in Adipose Tissue and Obesity

González-Casanova

Durán-Agüero

Caro-Fuentes

et al. 2021

IJMS

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Due to the inability to curb the excessive increase in the prevalence of obesity and overweight, it is necessary to comprehend in more detail the factors involved in the pathophysiology and to appreciate more clearly the biochemical and molecular mechanisms of obesity. Thus, understanding the biological regulation of adipose tissue is of fundamental relevance. Connexin, a protein that forms intercellular membrane channels of gap junctions and unopposed hemichannels, plays a key role in adipogenesis and in the maintenance of adipose tissue homeostasis. The expression and function of Connexin 43 (Cx43) during the different stages of the adipogenesis are differentially regulated. Moreover, it has been shown that cell–cell communication decreases dramatically upon differentiation into adipocytes. Furthermore, inhibition of Cx43 degradation or constitutive overexpression of Cx43 blocks adipocyte differentiation. In the first events of adipogenesis, the connexin is highly phosphorylated, which is likely associated with enhanced Gap Junction (GJ) communication. In an intermediate state of adipocyte differentiation, Cx43 phosphorylation decreases, as it is displaced from the membrane and degraded through the proteasome; thus, Cx43 total protein is reduced. Cx is involved in cardiac disease as well as in obesity-related cardiovascular diseases. Different studies suggest that obesity together with a high-fat diet are related to the production of remodeling factors associated with expression and distribution of Cx43 in the atrium.

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An Update on Connexin Gap Junction and Hemichannels in Diabetic Retinopathy

Cited by 14 publications

References 186 publications

Connexin 43: A Target for the Treatment of Inflammation in Secondary Complications of the Kidney and Eye in Diabetes

Connexin 43: A Target for the Treatment of Inflammation in Secondary Complications of the Kidney and Eye in Diabetes

Stimulation of C-Kit+ Retinal Progenitor Cells by Stem Cell Factor Confers Protection Against Retinal Degeneration

New Insights on the Role of Connexins and Gap Junctions Channels in Adipose Tissue and Obesity

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