Receptor for Advanced Glycation End Products in Health and Physiology

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The transmembrane protein receptor for advanced glycation end products (mRAGEs) is recognized as an immunoglobulin class of molecule. Mammalian cells produce a carboxy terminus truncated version of RAGE, either as endogenous soluble RAGE (esRAGE) or soluble RAGE (sRAGE), both being generated via proteolytic cleavage or alternative mRAGE-mRNA splicing. Through its extracellular domains (V, C1, and C2), RAGE interacts with seemingly unrelated ligands such as advanced glycation end products (AGEs), high mobility group box protein 1 (HMGB1), S100/calgranulin family, lysophosphatidic acid (LPA), oligomeric forms of amyloid beta peptide (Aβ-peptide), islet amyloid polypeptide (IAPP), attributing to the recognition as multi-ligand receptor. Under physiological conditions, lung tissues exhibit abundant RAGE expression compared to others, being involved in the development, spread, and homeostatic regulation, the prominent of which are lung alveolar type 1 (AT-1) epithelial cells. However, in pathophysiological conditions, supraphysiological expression of RAGE and its ligands and subsequent receptor-ligand interactions result in the aggravation of oxidative stress and inflammation, causing the propagation of various non-communicable disease conditions. The physiological RAGE expression may protect against non-small cell lung cancers (NSCLCs), as suppressed RAGE expression in lung tissues may complicate NSCLCs. The protective role of RAGE in lung tissues is surprisingly contrary to its activities in other cancers, which are unanimously characterized by its enhanced expression-driven propagation of the conditions. Anti-RAGE molecules including esRAGE/sRAGE attenuate RAGEdependent multiple diseased conditions.