Receptor for Advanced Glycation Endproducts (RAGE), Its Ligands, and Soluble RAGE: Potential Biomarkers for Diagnosis and Therapeutic Targets for Human Renal Diseases

Abstract

Receptor for advanced glycation endproducts (RAGE) is a multi-ligand receptor that is able to bind several different ligands, including advanced glycation endproducts, high-mobility group protein (B)1 (HMGB1), S-100 calcium-binding protein, amyloid-β-protein, Mac-1, and phosphatidylserine. Its interaction is engaged in critical cellular processes, such as inflammation, proliferation, apoptosis, autophagy, and migration, and dysregulation of RAGE and its ligands leads to the development of numerous human diseases. In this review, we summarize the signaling pathways regulated by RAGE and its ligands identified up to date and demonstrate the effects of hyper-activation of RAGE signals on human diseases, focused mainly on renal disorders. Finally, we propose that RAGE and its ligands are the potential targets for the diagnosis, monitoring, and treatment of numerous renal diseases.

Keywords: advanced glycosylation end-product receptor; kidney diseases; signal transduction.

Fig. 1

Structures of receptor for advanced glycation end products and its three main isoforms. Full-length receptor for advanced glycation endproducts (RAGE) has three different extracellular domains (V, C, C') and one cytosolic domain. Multi-ligands bind to the V-type domain and transduce signals through the intracellular domain. The N-truncated isoform lacks the V-type domain, which fails to have receptor-ligand interactions. The dominant-negative form has no cytosolic domain and is not able to transduce signals into the cell. Soluble RAGE is formed either by alternative splicing or protease activity and is secreted and prevents ligands from binding to RAGE. V, variable domain; C, constant domain.