Activation of NADPH oxidase by AGE links oxidant stress to altered gene expression via RAGE

Abstract

Engagement of the receptor for advanced glycation end products (RAGE) by products of nonenzymatic glycation/oxidation triggers the generation of reactive oxygen species (ROS), thereby altering gene expression. Because dissection of the precise events by which ROS are generated via RAGE is relevant to the pathogenesis of complications in AGE-related disorders, such as diabetes and renal failure, we tested the hypothesis that activation of NADPH oxidase contributed, at least in part, to enhancing oxidant stress via RAGE. Here we show that incubation of human endothelial cells with AGEs on the surface of diabetic red blood cells, or specific AGEs, (carboxymethyl)lysine (CML)-modified adducts, prompted intracellular generation of hydrogen peroxide, cell surface expression of vascular cell adhesion molecule-1, and generation of tissue factor in a manner suppressed by treatment with diphenyliodonium, but not by inhibitors of nitric oxide. Consistent with an important role for NADPH oxidase, although macrophages derived from wild-type mice expressed enhanced levels of tissue factor upon stimulation with AGE, macrophages derived from mice deficient in a central subunit of NADPH oxidase, gp91phox, failed to display enhanced tissue factor in the presence of AGE. These findings underscore a central role of NADPH oxidase in AGE-RAGE-mediated generation of ROS and provide a mechanism for altered gene expression in AGE-related disorders.

The HMG-CoA reductase inhibitor rosuvastatin and the angiotensin receptor antagonist candesartan attenuate atherosclerosis in an apolipoprotein E-deficient mouse model of diabetes via effects on advanced glycation, oxidative stress and inflammation

“…Although such an effect on the AGE/RAGE axis has previously been observed in cell culture experiments [44] and postulated to be important in type 2 diabetic patients for plaque stabilisation [43], this is the first study to demonstrate effects of a statin on the AGE/RAGE pathway in diabetesaccelerated atherosclerosis. Indeed, our study suggests that statins may reduce AGE accumulation and thereby reduce activation of NAD(P)H oxidase, thus linking oxidant stress to altered gene expression via RAGE, as previously suggested in vitro and in gp91phox-deficient mice [45]. Furthermore, this is the first report to describe superior effects on the AGE/RAGE pathway, particularly in the vascular wall, by a combination regimen consisting of candesartan and rosuvastatin.…”

Synergistic action of advanced glycation end products and endogenous nitric oxide leads to neuronal apoptosis in vitro: A new insight into selective nitrergic neuropathy in diabetes

“…The induction of cell death by both AGEs and NO has been associated previously with oxidative stress [32,33,34,35]. The source of oxidative stress in diabetes mellitus, however, has not been fully elucidated.…”

“…Whether AGEs induce ROS formation directly [38] or through their receptor, RAGE [34] has been debated. We think that in our experiments ROS are generated through RAGE because of two reasons: Firstly, the measurement of ROS was performed after AGEs were removed from the medium, suggesting that an intracellular mechanism of ROS formation must have been switched on by AGEs, most probably thorough RAGE.…”

α-Tocopherol Protects Against Oxidative Stress in the Fragile X Knockout Mouse: an Experimental Therapeutic Approach for the Fmr1 Deficiency

“…It catalyzes the reduction of molecular oxygen to form superoxide (O 2À ), a potent-free radical that has a physiological function in the nervous system. NADPH-oxidase enzyme activity is regulated by four cytosolic subunits: p47 phox , p67 phox , p40 phox , and small Rac-GTPase proteins (Wautier et al, 2001). A major concept in redox signaling is that although NADPH-oxidase-derived ROS are necessary for normal cellular function, excessive production leads to oxidative stress and can contribute to pathological diseases.…”