2016 ATVB Plenary Lecture

Abstract

The receptor for advanced glycation endproducts (RAGE) interacts with a unique repertoire of ligands that form and collect in the tissues and circulation in diabetes, aging, inflammation, renal failure and obesity. RAGE is expressed on multiple cell types linked to tissue perturbation in these settings. This Brief Review focuses on the role of RAGE in monocytes/macrophages and how RAGE ligand engagement on these cells mediates seminal changes in monocyte/macrophage migration, oxidative stress, cholesterol efflux and pro- vs. anti-inflammatory cues that signal to tissue damage. Studies using mice devoid of Ager (gene encoding RAGE) or pharmacological antagonists of RAGE are protective in animal models of diabetes, atherosclerosis, and high fat diet-induced obesity, in least in part through key roles in monocytes/macrophages. RAGE signal transduction requires the interaction of RAGE cytoplasmic domain with the formin, DIAPH1 and novel antagonists of this interaction show significant promise in attenuation of the maladaptive effects of RAGE ligands in cellular and in vivo models. Finally, this Brief Review discusses evidence for RAGE axis perturbation in human monocytes/macrophages and how tracing RAGE activity in these cells may identify target engagement biomarkers of RAGE antagonism for future clinical trials.

Diabetes, Hypertension, and Cardiovascular Disease: Clinical Insights and Vascular Mechanisms

“…As such, urinary and plasma AGE levels and soluble RAGE may act as biomarkers for vascular disease in diabetes. 45 …”

RAGE signalling in obesity and diabetes: focus on the adipose tissue macrophage

“…The process of AGEs production is through non-enzymatic glycation of macromolecules with a reducing sugar, such as glucose or fructose. This accumulation can occur endogenously (hyperglycaemia, ageing, inflammation, renal failure, obesity and oxidative stress) or exogenously (high fat diet, processed food, chronic alcohol consumption and tobacco)[ 1 ]. The average body glycosylation reaction can proceed slowly.…”

“…The average body glycosylation reaction can proceed slowly. Once the body is ageing or continues to have high blood sugar, the glycosylation reaction quickly accelerates, thereby forming a large number of AGEs[ 1 ]. Among the various receptors of AGEs found at present, RAGE is a crucial receptor for AGEs to exert the primary mechanism of cells.…”

“…RAGE deficient mice fed on a high-fat diet are significantly lower in body weight, epididymal fat weight, and large size than WT mice, indicating that for high-fat diet-induced obesity, the RAGE knockout mice show apparent resistance [ 10 ]. More recently, HMGB1 was proposed to be an adipokine, and expressed 2-fold more in adipose tissue from obese individuals that acts as an innate pro-inflammatory mediator in WAT, which may be associated with insulin resistance and metabolic syndrome [ 1 , 12 , 13 ]. In the human body, the imbalance between energy intake and consumption will cause a series of diseases such as obesity.…”

“…Besides, they also confirmed in human adipose tissue that RAGE and CML-modified proteins are significantly expressed in adipocytes, CD68+ macrophages, and CD31-positive endothelial cells. The expression levels of CD163, IL-10, CD209d, Arg1, and CD209e in the visceral adipose tissue of Ager-/-mice fed a high-fat diet were significantly higher than those of wild-type mice [ 1 ], suggesting that RAGE can promote the development of obesity under the condition of high-fat diet feeding, and also promote the entry of F4/80-expressing macrophages into visceral fat. Although RAGE plays an essential role in obesity-induced by a high-fat diet, such as regulating body weight and adipose tissue macrophages, the exact mechanism of action is still unclear, and active research is needed to explore the role of RAGE in ATMs.…”