Effects of high glucose-induced downregulation of connexin 43 on tight junction protein expression and its role in the pathogenesis of diabetic retinopathy
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Diabetes is a disease characterized by high blood glucose levels that result from a defect in the body’s inability to produce or utilize insulin. This disease increases the risk of long-term health problems and affects multiple organ systems; one complication being diabetic retinopathy (DR) that causes changes in the blood vessels of the retina. Diabetic retinopathy is the leading cause of blindness in the working age population. Early events in the pathogenesis of diabetic retinopathy are characterized by retinal vascular cell loss and excess retinal capillary leakage. Studies have shown that the retinal vascular cell loss occurs by programmed cell death while excess permeability develops at least in part through compromised tight junctions. Studies, including those from our laboratory, have also established that high glucose or diabetes reduces a specific protein, Cx43, found in intercellular communication channels or gap junctions, and contributes to the development of programmed cell death. It is currently unknown if there is an association between high glucose- or diabetes-induced Cx43 downregulation and excess permeability. Importantly, previous studies have shown that reduced Cx43 can promote excess permeability, but the mechanism underlying this phenomenon is not well understood. In this study, the effects of reduced Cx43 expression on proteins involved in cell-cell adhesion, or tight junctions, was examined. Specifically, experimentally induced Cx43 downregulation by a gene silencing technique affected the expression of tight junction proteins (ZO-1, occludin, claudin-5) in rat retinal endothelial cells. ZO-1 and occludin protein levels were decreased while claudin-5 levels were increased. In addition, permeability was increased when Cx43 was downregulated. These observations suggest that expression levels of Cx43 regulate barrier characteristics by influencing the expression of tight junction proteins. Findings from this study provide an insight into how high glucose-induced Cx43 downregulation compromises endothelial barrier characteristics through modulation of tight junction proteins.
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