The interaction between RAGE and its ligands is thought to result in pro-inflammatorygene activation.[6][7] Due to an enhanced level of RAGE ligands in diabetes or other chronic disorders, this receptor is hypothesised to have a causative effect in a range of inflammatory diseases such as diabetic complications, Alzheimer's disease and even some tumors.
Isoforms of the RAGE protein, which lack the transmembrane and the signaling domain (commonly referred to as soluble RAGE or sRAGE) are hypothesized to counteract the detrimental action of the full-length receptor and are hoped to provide a means to develop a cure against RAGE-associated diseases.
The primary transcript of the human RAGE gene (pre-mRNA) is thought to be alternatively spliced. So far about 6 isoforms including the full length transmembrane receptor have been found in different tissues such as lung, kidney, brain etc. Five of these 6 isoforms lack the transmembrane domain and are thus believed to be secreted from cells. Generally these isoforms are referred to as sRAGE (soluble RAGE) or esRAGE (endogenous secretory RAGE). One of the isoforms lacks the V-domain and is thus believed not to be able to bind RAGE ligands.
RAGE exists in the body in two forms: a membrane-bound form known as mRAGE, and a soluble form, known as sRAGE. mRAGE has three domains, and sRAGE has only the extracellular domain. sRAGE is either the product of alternative splicing or the product of proteolytic cleavage of mRAGE.[10]
The full receptor consists of the following domains: The cytosolic domain, which is responsible for signal transduction, the transmembrane domain which anchors the receptor in the cell membrane, the variable domain which binds the RAGE ligands, and two constant domains.[citation needed]
RAGE is able to bind several ligands and therefore is referred to as a pattern-recognition receptor. Ligands which have so far been found to bind RAGE are:
RAGE has been linked to several chronic diseases, which are thought to result from vascular damage. The pathogenesis is hypothesized to include ligand binding, upon which RAGE signals activation of nuclear factor kappa B (NF-κB). NF-κB controls several genes involved in inflammation. RAGE itself is upregulated by NF-κB. Given a condition in which there is a large amount of a RAGE ligand present (e.g. AGE in diabetes or amyloid-β-protein in Alzheimer's disease) this establishes a positive feed-back cycle, which leads to chronic inflammation. This chronic condition is then believed to alter the micro- and macrovasculature, resulting in organ damage or even organ failure.[16] However, whilst RAGE is up-regulated in inflammatory conditions, it is down-regulated in lung cancer and pulmonary fibrosis.[10] Diseases that have been linked to RAGE are: [citation needed]
RAGE is expressed at the highest levels in the lung compared to other tissues, in particular in alveolar type I cells, and is lost in idiopathic pulmonary fibrosis (IPF) indicating that expression and regulation of RAGE in the pulmonary system differs from that in the vascular system. Blockade/knockdown of RAGE resulted in impaired cell adhesion, and increased cell proliferation and migration[22]
vTv Therapeutics (formerly TransTech Pharma) sponsored a Phase 3 clinical trial of their RAGE inhibitor Azeliragon (TTP488) for mild Alzheimer's disease.[27][28] These trials were halted in 2018.[29]
Besides RAGE there are other receptors which are believed to bind advanced glycation endproducts. However, these receptors could play a role in the removal of AGE rather than in signal transduction as is the case for RAGE. Other AGE receptors are:
^Hudson BI, Hofman MA, Bucciarelli L, Wendt T, Moser B, Lu Y, Qu W, Stern DM, D'Agati V, Yan SD, Yan SF, Grant PJ (2002). "Glycation and diabetes: The RAGE connection"(PDF). Current Science. 83 (12): 1515–1521.
^Penumutchu SR, Chou RH, Yu C (November 2014). "Interaction between S100P and the anti-allergy drug cromolyn". Biochemical and Biophysical Research Communications. 454 (3): 404–9. doi:10.1016/j.bbrc.2014.10.048. PMID25450399.
^Hermani A, De Servi B, Medunjanin S, Tessier PA, Mayer D (January 2006). "S100A8 and S100A9 activate MAP kinase and NF-kappaB signaling pathways and trigger translocation of RAGE in human prostate cancer cells". Experimental Cell Research. 312 (2): 184–97. doi:10.1016/j.yexcr.2005.10.013. PMID16297907.
^Mahajan N, Mahmood S, Jain S, Dhawan V (September 2013). "Receptor for advanced glycation end products (RAGE), inflammatory ligand EN-RAGE and soluble RAGE (sRAGE) in subjects with Takayasu's arteritis". International Journal of Cardiology. 168 (1): 532–4. doi:10.1016/j.ijcard.2013.01.002. PMID23398829.
^Queisser MA, Kouri FM, Königshoff M, Wygrecka M, Schubert U, Eickelberg O, Preissner KT (September 2008). "Loss of RAGE in pulmonary fibrosis: molecular relations to functional changes in pulmonary cell types". American Journal of Respiratory Cell and Molecular Biology. 39 (3): 337–45. doi:10.1165/rcmb.2007-0244OC. PMID18421017.
^Han YT, Choi GI, Son D, Kim NJ, Yun H, Lee S, Chang DJ, Hong HS, Kim H, Ha HJ, Kim YH, Park HJ, Lee J, Suh YG (November 2012). "Ligand-based design, synthesis, and biological evaluation of 2-aminopyrimidines, a novel series of receptor for advanced glycation end products (RAGE) inhibitors". Journal of Medicinal Chemistry. 55 (21): 9120–35. doi:10.1021/jm300172z. PMID22742537.
^Han YT, Kim K, Choi GI, An H, Son D, Kim H, Ha HJ, Son JH, Chung SJ, Park HJ, Lee J, Suh YG (May 2014). "Pyrazole-5-carboxamides, novel inhibitors of receptor for advanced glycation end products (RAGE)". European Journal of Medicinal Chemistry. 79: 128–42. doi:10.1016/j.ejmech.2014.03.072. PMID24727489.
^Han YT, Kim K, Son D, An H, Kim H, Lee J, Park HJ, Lee J, Suh YG (February 2015). "Fine tuning of 4,6-bisphenyl-2-(3-alkoxyanilino)pyrimidine focusing on the activity-sensitive aminoalkoxy moiety for a therapeutically useful inhibitor of receptor for advanced glycation end products (RAGE)". Bioorganic & Medicinal Chemistry. 23 (3): 579–87. doi:10.1016/j.bmc.2014.12.003. PMID25533401.
^"Azeliragon". vTv Therapeutics. Retrieved 23 July 2015.
^Clinical trial number NCT02080364 for "Evaluation of the Efficacy and Safety of Azeliragon (TTP488) in Patients With Mild Alzheimer's Disease (STEADFAST)" at ClinicalTrials.gov
Nawroth P, Bierhaus A, Marrero M, Yamamoto H, Stern DM (February 2005). "Atherosclerosis and restenosis: is there a role for RAGE?". Current Diabetes Reports. 5 (1): 11–6. doi:10.1007/s11892-005-0061-9. PMID15663911. S2CID23298217.
Overview of all the structural information available in the PDB for UniProt: Q15109 (Human Advanced glycosylation end product-specific receptor) at the PDBe-KB.
Overview of all the structural information available in the PDB for UniProt: Q62151 (Mouse Advanced glycosylation end product-specific receptor) at the PDBe-KB.