Advanced glycosylation end product-specific receptor (RAGE) (RAGE)

The Advanced glycosylation end product-specific receptor (RAGE) is a multiligand transmembrane receptor of the immunoglobulin superfamily that recognizes various molecules associated with cellular stress and damage, including advanced glycation end products (AGEs), S100/calgranulins, and High Mobility Group Box 1 (HMGB1) [1, 8]. Activation of the RAGE signaling pathway initiates a sustained pro-inflammatory response, primarily through the activation of the transcription factor NF-κB, which leads to the production of reactive oxygen species and pro-inflammatory cytokines [4, 20]. This pathway plays a critical role in the pathogenesis of chronic inflammatory conditions, particularly diabetic complications such as nephropathy and retinopathy, as well as neurodegenerative disorders like Alzheimer's disease, where RAGE mediates the transport of amyloid-beta across the blood-brain barrier [10, 14, 22]. Therapeutic strategies targeting RAGE involve small molecule antagonists, decoy receptors (sRAGE), and inhibitors of its intracellular adaptor proteins like DIAPH1 to mitigate chronic tissue damage and inflammation [6, 11, 20]. While RAGE is a promising target for metabolic and neurodegenerative diseases, its role in innate immunity necessitates careful consideration of safety during long-term inhibition [5, 10].

Other names

Receptor for advanced glycation end productsAGERSCARJ1Advanced glycosylation end-product specific receptorsRAGE (soluble form)esRAGE (endogenous secretory form)

Competitive inhibition of ligand binding to the extracellular V-domain of RAGE or disruption of the interaction between the RAGE cytoplasmic tail and the intracellular effector DIAPH1 to block downstream pro-inflammatory and pro-oxidative signaling cascades [6, 7, 11].