Hyperglycemia-Induced Reactive Oxygen Species Increase Expression of the Receptor for Advanced Glycation End Products (RAGE) and RAGE Ligands

摘要

Objective-RAGE interacts with the endogenous ligands S100 calgranulins and high mobility group box 1 (HMGB1) to induce inflammation. Since hyperglycemia-induced reactive oxygen species (ROS) activate many pathways of diabetic tissue damage, the effect of these ROS on RAGE and RAGE ligand expression was evaluated.rnResearch Design And Methods-Expression of RAGE, S100A8, S100A12, and HMGB1 was evaluated in human aortic endothelial cells (HAECs) incubated in normal glucose, high glucose, and high glucose after overexpression of either uncoupling protein 1 (UCP1), superoxide dismutase 2 (S0D2), or glyoxalase 1 (GLO1). Expression was also evaluated in normal glucose after knockdown of GLO1. Expression was next evaluated in high glucose after knockdown of nuclear factor (NF)-kB p65 (RAGE) and after knockdown of activated pro-tein-1 (AP-1) (S100A8, S100A12, and HMGB1), and chromatin immunoprecipitation (CMP) was performed ± GL01 overexpression for NFkB p65 (RAGE promoter) and AP-1 (S100A8, S100A12, and HMGB1 promoters). Finally, endothelial cells from nondiabetic mice, STZ diabetic mice, and STZ diabetic mice treated with the superoxide dismutase mimetic Mn(III)tet-rakis(4-benzoic acid)porphyrin chloride (MnTBAP) were evaluated.rnResults-High glucose increased RAGE, S100A8, S100A12, and HMGB1 expression, which was normalized by overexpression of UCP1, S0D2, or GL01. GL01 knockdown mimicked the effect of high glucose, and in high glucose, overexpression of GL01 normalized increased binding of NFkB p65 and AP-1. Diabetes increased RAGE, S100A8, and HMGB1 expression, and MnTBAP treatment normalized this.rnConclusions-These Results show that hyperglycemia-induced ROS production increases expression of RAGE and RAGE ligands. This eifect is mediated by ROS-induced methylglyoxal, the major substrate of glyoxalase 1.