Abstract
AbstractPurpose To test the hypothesis that increased expression of proinflammatory cytokine high‐mobility group box‐1 (HMGB1) in epiretinal membranes and vitreous fluid from patients with proliferative diabetic retinopathy and in retinas of diabetic rats plays a pathogenetic role in mediating diabetes‐induced retinal neuropathy.Methods Retinas of 1‐month diabetic rats and HMGB1 intravitreally injected normal rats were studied using Western blot analysis, RT‐PCR and glutamate assay. In addition, we studied the effect of the HMGB1 inhibitor glycyrrhizin on diabetes‐induced biochemical changes in the retina.Results Diabetes and intravitreal injection of HMGB1 in normal rats induced significant upregulation of HMGB1 protein and mRNA, activated extracellular signal‐regulated kinase 1 and 2 (ERK1/2) cleaved caspase‐3 and glutamate and significant downregulation of synaptophysin, tyrosine hydroxylase, glutamine synthetase and glyoxalase 1. Constant glycyrrhizin intake from the onset of diabetes did not affect the metabolic status of the diabetic rats, but it significantly attenuated diabetes‐induced upregulation of HMGB1 protein and mRNA, activated ERK1/2 , cleaved caspase‐3 and glutamate. In the glycyrrhizin‐fed diabetic rats, the decrease in synaptophysin, tyrosine hydoxylase and glyoxalase 1 caused by diabetes was significantly attenuated.Conclusion These findings suggest that early retinal neuropathy of diabetes involves upregulated expression of HMGB1 and can be ameliorated by inhibition of HMGB1.
Highlights
Diabetic retinopathy (DR), a vision-threatening disease, has classically been regarded as a disease of the retinal microvasculature and a consequence of vascular cell damage
We investigated the pathological role of High-mobility group box-1 (HMGB1) in diabetes-induced retinal neuropathy
Our data show that intravitreal injection of HMGB1 in normal rats mimics the effect of diabetes
Summary
Diabetic retinopathy (DR), a vision-threatening disease, has classically been regarded as a disease of the retinal microvasculature and a consequence of vascular cell damage. High-mobility group box-1 (HMGB1) is a nonhistone DNA-binding nuclear protein that has been implicated in diverse intracellular functions, including the stabilization of nucleosomal structures and the facilitation of gene transcription. Extracellular HMGB1 functions as a proinflammatory cytokine and triggers the inflammatory response through the activation of multiple receptors such as the receptor for advanced glycation end products (RAGE), toll-like receptor-2 (TLR2), and TLR4 leading to activation of the transcription factors extracellular signal-regulated kinase 1 and 2 (ERK1/2) and nuclear factor Kappa B (NF-κB), which may alter gene transcription and lead to the upregulation of proinflammatory cytokines, chemokines, and adhesion molecules and intensifies cellular oxidative stress [5,6,7,8,9,10], processes that may play a role in the pathogenesis of diabetic retinal neurodegeneration and dysfunction. Strong evidence indicates that chronic, low-grade inflammation is implicated
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