The proinflammatory cytokine high‐mobility group box‐1 mediates retinal neuropathy induced by diabetes

Abstract

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. 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. 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 hydroxylase, and glyoxalase 1 caused by diabetes was significantly attenuated. These findings suggest that early retinal neuropathy of diabetes involves upregulated expression of HMGB1 and can be ameliorated by inhibition of HMGB1.

Mutual enhancement between high-mobility group box-1 and NADPH oxidase-derived reactive oxygen species mediates diabetes-induced upregulation of retinal apoptotic markers

“…In addition, we demonstrated that HMGB1 expression was upregulated in the retinas of diabetic mice and rats [1,26] and that HMGB1 plays a key role in mediating diabetes-induced retinal vasculopathy and neuropathy [22,1,26]. Five key findings emerged from this study.…”

“…4c, d). In previous studies, we demonstrated that constant glycyrrhizin intake attenuated diabetes-induced upregulation of HMGB1 in the retinas of rats [1]. Spectrofluorometric analysis demonstrated significant upregulation of ROS generation in diabetic retinas compared to nondiabetic retinas.…”

“…Intravitreal administration of HMGB1 upregulates ROS generation and the expression of Nox2, PARP-1 and cleaved caspase-3 in the retinas Effects of HMGB1 on retinal ROS level and the expression of Nox2, PARP-1 and cleaved caspase- In previous studies, we demonstrated that intravitreal administration of HMGB1 significantly upregulates HMGB1 in the retinas of normal rats [1,26]. DCFH-DA assay revealed that ROS levels in the retinas of HMGB1-injected animals were significantly higher compared to the values obtained from the contralateral eye that received PBS alone (p = 0.036) (Fig.…”

“…In addition, we demonstrated that diabetes induced significant upregulation of the expression of HMGB1 and RAGE in the retinas of rats and mice [11,26]. Furthermore, a great deal of evidence has indicated the critical importance of HMGB1 in mediating inflammation, breakdown of the blood-retinal barrier, oxidative stress, apoptosis and neuropathy in the diabetic retina [1,26,36]. However, molecular mechanisms linking between HMGB1 and ROS generation and apoptotic signaling pathways in the diabetic retina are still not well understood.…”

High Mobility Group Box1 Inhibitor Glycyrrhizic Acid Attenuates Kidney Injury in Streptozotocin-Induced Diabetic Rats

“…GA treatment markedly inhibits NLRP3 inflammasome activation, diet-induced adipose tissue inflammation and IL-1β and caspase-1 production in white adipose tissue in ex vivo cultures [14]. GA protects the retinal vascular barrier and prevents retinal neuropathy by inhibiting the HMGB1-related inflammatory response and inactivating ERK(1/2) and NF-κB in the diabetic retina (DR) [15,16]. Several recent studies [17,18] have indicated that HMGB1 is activated in type 2 diabetes mellitus patients and high glucose-induced mesangial cells and that HMGB1 promotes AGEinduced expression of TGF-β and connective tissue growth factor (CTGF) in renal tubular epithelial cells.…”