Glycation & the RAGE axis: targeting signal transduction through DIAPH1

Abstract

Introduction The consequences of chronic disease are vast and unremitting; hence, understanding the pathogenic mechanisms mediating such disorders holds promise to identify therapeutics and diminish the consequences. The ligands of the receptor for advanced glycation end products (RAGE) accumulate in chronic diseases, particularly those characterized by inflammation and metabolic dysfunction. Although first discovered and reported as a receptor for advanced glycation end products (AGEs), the expansion of the repertoire of RAGE ligands implicates the receptor in diverse milieus, such as autoimmunity, chronic inflammation, obesity, diabetes, and neurodegeneration. Areas covered This review summarizes current knowledge regarding the ligand families of RAGE and data from human subjects and animal models on the role of the RAGE axis in chronic diseases. The recent discovery that the cytoplasmic domain of RAGE binds to the formin homology 1 (FH1) domain, DIAPH1, and that this interaction is essential for RAGE ligand-stimulated signal transduction, is discussed. Finally, we review therapeutic opportunities targeting the RAGE axis as a means to mitigate chronic diseases. Expert commentary With the aging of the population and the epidemic of cardiometabolic disease, therapeutic strategies to target molecular pathways that contribute to the sequelae of these chronic diseases are urgently needed. In this review, we propose that the ligand/RAGE axis and its signaling nexus is a key factor in the pathogenesis of chronic disease and that therapeutic interruption of this pathway may improve quality and duration of life.

Receptor for Advanced Glycation End Products (RAGE) and Mechanisms and Therapeutic Opportunities in Diabetes and Cardiovascular Disease: Insights From Human Subjects and Animal Models

“…Hence, AGE interaction with RAGE ensues both from endogenously-formed AGE adducts, as well as from dietary AGE sources. RAGE is expressed on multiple types of cells, such as vascular cells, immune cells, neurons, cardiomyocytes, adipocytes, glomerular epithelial cells or podocytes, lung epithelial cells, and a wide range of transformed cells, both in animal models and human subjects (3)(4)(5).…”

2016 ATVB Plenary Lecture

“…RAGE, a member of the immunoglobulin superfamily of cell surface molecules, was originally discovered for its ability to bind to and transduce the biological effects of advanced glycation endproducts (AGEs), which accumulate in settings such as hyperglycemia, aging, inflammation, renal failure and oxidative stress 1, 2 . AGEs are an heterogeneous group of modified molecules, which form particularly on lysine and arginine amino acid residues.…”

“…RAGE is expressed on multiple cell types implicated in cardiovascular disease (CVD), such as vascular cells (endothelial cells (ECs) and smooth muscle cells (SMCs)) and immune cells such as monocytes/macrophages, T and B lymphocytes and neutrophils 1, 2, 12 . This Brief Review, focusing on RAGE and monocytes/macrophages in cardiometabolic disorders, will detail the evidence that points to roles for RAGE not only in recruitment of these key cells in atherosclerosis and obesity but also to their expression of pro-inflammatory mediators and reduced expression of molecules linked to cholesterol efflux.…”

Advanced Glycation Endproducts form During Ovalbumin Digestion in the Presence of Fructose

“…RAGE is involved in many inflammatory conditions [16][17][18][19]. RAGE is a pattern recognition receptor that binds AGE, among several ligands related to primary immunity [18][19].…”

“…RAGE is a pattern recognition receptor that binds AGE, among several ligands related to primary immunity [18][19]. AGEs may be endogenous and exogenous [9].…”