High-Mobility Group Box-1 Protein Mediates the Regulation of Signal Transducer and Activator of Transcriptiwn-3 in the Diabetic Retina and in Human Retinal Muller Cells

Purpose: The expression of high-mobility group box -1 (HMGB1) and signal transducer and activator of transcription -3 (STAT-3) is upregulated in the diabetic retina. We hypothesized that the activation of STAT-3 is under the control of HMGB1. Methods: Retinas from 1-month-old diabetic rats and from normal rats intravitreally injected with HMGB1 and human retinal Muller glial cells (M10-M1) stimulated with HMGB1 or high glucose were studied by Western blot analysis and immunofluorescence. We also studied the effect of the HMGB1 inhibitor glycyrrhizin (GA) on high-glucose-induced pSTAT-3 nuclear translocation and upregulation in Muller cells and on pSTAT-3 expression in the retinas of diabetic rats (n = 7-10 in each group). In addition, we studied the effect of STAT-3 inhibitor on the HMGB1-induced induction of vascular endothelial growth factor (VEGF) by Muller cells and human retinal microvascular endothelial cell (HRMEC) migration. Results: Treatment of retinal Muller cells with recombinant HMGB1 induced nuclear translocation of pSTAT-3 but did not alter pSTAT-3 expression. High glucose induced a significant upregulation of HMGB1 and pSTAT-3 upregulation and nuclear translocation in retinal Muller cells. GA co-treatment normalized the high-glucose-induced upregulation of HMGB1 and pSTAT-3 upregulation and nuclear translocation in Muller cells. Intravitreal administration of HMGB1 in normal and diabetic rats upregulated pSTAT-3 expression in the retina. GA attenuated the diabetes-induced upregulation of pSTAT-3 in the retina. The STAT-3 inhibitor attenuated HMGB1-induced VEGF upregulation by Muller cells and HRMEC migration. Conclusions: The results suggest a role for HMGB1 in the modulation of STAT-3 expression in the diabetic retina. (C) 2016 S. Karger AG, Basel