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RAGE (receptor)

From Wikipedia, the free encyclopedia

"AGER" redirects here. For other uses, see Ager (disambiguation).
AGER
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesAGER, Ager, RAGE, SCARJ1, advanced glycosylation end product-specific receptor, advanced glycosylation end-product specific receptor, sRAGE
External IDsOMIM: 600214; MGI: 893592; HomoloGene: 883; GeneCards: AGER; OMA:AGER - orthologs
Orthologs
SpeciesHumanMouse
Entrez

177

11596

Ensembl

ENSMUSG00000015452

UniProt

Q15109

Q62151

RefSeq (mRNA)

NM_001271422
NM_001271423
NM_001271424
NM_007425

RefSeq (protein)

NP_001258351
NP_001258352
NP_001258353
NP_031451

Location (UCSC)Chr 6: 32.18 – 32.18 MbChr 17: 34.82 – 34.82 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse
Schematic of the relation between an immunoglobulin and RAGE
Schematic of the RAGE gene and its products

RAGE (receptor for advanced glycation endproducts), also called AGER, is a 35 kilodalton transmembrane receptor[5] of the immunoglobulin super family which was first characterized in 1992 by Neeper et al.[6] Its name comes from its ability to bind advanced glycation endproducts (AGE), which include chiefly glycoproteins, the glycans of which have been modified non-enzymatically through the Maillard reaction. In view of its inflammatory function in innate immunity and its ability to detect a class of ligands through a common structural motif, RAGE is often referred to as a pattern recognition receptor. RAGE also has at least one other agonistic ligand: high mobility group protein B1 (HMGB1). HMGB1 is an intracellular DNA-binding protein important in chromatin remodeling which can be released by necrotic cells passively, and by active secretion from macrophages, natural killer cells, and dendritic cells.

The interaction between RAGE and its ligands is thought to result in pro-inflammatory gene activation.[7][8] 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.

Gene and polymorphisms

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The RAGE gene lies within the major histocompatibility complex (MHC class III region) on chromosome 6 and comprises 11 exons interlaced by 10 introns. Total length of the gene is about 1400 base pairs (bp) including the promoter region, which partly overlaps with the PBX2 gene.[9] About 30 polymorphisms are known most of which are single-nucleotide polymorphisms.[10]

RNA and alternative splicing

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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.

Structure

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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.[11]

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]

Ligands

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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 Ligands and Binding Mechanism

The receptor for advanced glycation end products (RAGE) is a multiligand member of the immunoglobulin superfamily, originally identified due to its ability to bind advanced glycation end products (AGEs). AGEs accumulate in various chronic conditions such as diabetes and renal failure. However, RAGE also binds other ligands, notably proteins of the S100/calgranulin family, such as EN-RAGE and S100B, which play significant roles in inflammatory processes.[17]

RAGE ligands interact with the receptor through its extracellular domain, triggering a cascade of intracellular signaling pathways. These pathways lead to the activation of key transcription factors like nuclear factor kappa B (NF-κB), which is central to the expression of proinflammatory cytokines, adhesion molecules (such as VCAM-1 and ICAM-1), and other mediators of inflammation.[18] Upon binding ligands like EN-RAGE or S100B, RAGE stimulates various inflammatory responses, including endothelial cell activation, mononuclear cell migration, and the production of cytokines such as TNF-α and IL-1β.[19]

These interactions between RAGE and its ligands contribute to chronic inflammatory conditions, including atherosclerosis, Alzheimer's disease, and diabetic complications. Inhibiting the RAGE-ligand interaction—through the use of soluble RAGE (sRAGE) or specific antibodies—can suppress these inflammatory responses, offering potential therapeutic strategies.[20]

RAGE and disease

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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.[21] However, whilst RAGE is up-regulated in inflammatory conditions, it is down-regulated in lung cancer and pulmonary fibrosis.[11] Diseases that have been linked to RAGE are: [citation needed]

Role of RAGE in Diabetes and Cardiovascular Disease.

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[27]

The Receptor for Advanced Glycation End Products (RAGE) plays a pivotal role in the pathogenesis of both diabetes and cardiovascular disease (CVD). This multi-ligand receptor belongs to the immunoglobulin superfamily and primarily binds to advanced glycation end products (AGEs), which are formed through the non-enzymatic glycation of proteins and lipids. In diabetes, hyperglycemia accelerates AGE formation, leading to a pro-inflammatory and pro-oxidative state that exacerbates vascular damage and immune cell dysfunction.[28][29]

Role in Diabetes

In both type 1 and type 2 diabetes, RAGE contributes significantly to microvascular and macrovascular complications. The receptor is highly expressed in diabetic blood vessels, cardiomyocytes, podocytes, and immune cells, co-localizing with its ligands (AGEs, S100/calgranulins, and high-mobility group box 1 [HMGB1]). This co-localization results in chronic cellular stress and inflammation, distinct from the transient responses seen in acute infections.[30]

In diabetes, RAGE engagement exacerbates conditions like diabetic nephropathy and retinopathy. Studies in diabetic mouse models have demonstrated that blocking RAGE with soluble forms of the receptor (sRAGE) can mitigate these complications by reducing mesangial sclerosis, basement membrane thickening, and endothelial damage(nihms799448). The receptor's interaction with AGEs and S100 proteins contributes to the progression of atherosclerosis in diabetes, which is marked by increased lesion complexity, macrophage accumulation, and vascular inflammation.[31]

Role in Cardiovascular Disease

RAGE also plays a central role in the development of cardiovascular diseases, particularly atherosclerosis. It is highly expressed in both diabetic and non-diabetic atherosclerotic plaques, but expression is more pronounced in diabetic patients. The receptor's activation in smooth muscle cells, endothelial cells, and macrophages promotes the development of atherosclerotic lesions through mechanisms involving oxidative stress, inflammatory signaling, and immune cell recruitment.[32]

RAGE-mediated signaling enhances vascular inflammation, endothelial dysfunction, and plaque instability. Animal studies have shown that blocking RAGE in diabetic models reduces lesion formation and improves vascular function without altering blood glucose levels.[33][34]

Therapeutic Implications

Given its prominent role in both diabetes and CVD, RAGE is a promising therapeutic target. Preclinical and clinical studies are exploring RAGE antagonism to treat these conditions. Blocking RAGE signaling, either through pharmacological inhibitors or soluble decoy receptors like sRAGE, has shown potential in reducing vascular complications in diabetic patients. These strategies may offer new ways to manage the chronic inflammation and oxidative stress that drive both diabetic complications and cardiovascular disease progression.[35]

RAGE's role in diabetes and cardiovascular disease highlights the importance of its signaling pathway in mediating chronic inflammation and vascular damage. Targeting RAGE could offer a promising approach to mitigating the burden of these diseases, particularly in patients with diabetes, where current therapies may fall short in preventing cardiovascular complications.

Inhibitors

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A number of small molecule RAGE inhibitors or antagonists have been reported.[36][37][38][39]

Azeliragon
vTv Therapeutics (formerly TransTech Pharma) sponsored a Phase 3 clinical trial of their RAGE inhibitor Azeliragon (TTP488) for mild Alzheimer's disease.[40][41] These trials were halted in 2018.[42]

AGE receptors

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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:

  • SR-A (Macrophage scavenger receptor Type I and II)
  • OST-48 (Oligosaccharyl transferase-4) (AGE-R1)
  • 80 K-H phosphoprotein (Proteinkinase C substrate) (AGE-R2)
  • Galectin-3 (AGE-R3)
  • LOX-1 (Lectin-like oxidized low density lipoprotein receptor-1)
  • CD36

References

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  1. ^ a b c ENSG00000206320, ENSG00000231268, ENSG00000234729, ENSG00000229058, ENSG00000204305, ENSG00000230514 GRCh38: Ensembl release 89: ENSG00000237405, ENSG00000206320, ENSG00000231268, ENSG00000234729, ENSG00000229058, ENSG00000204305, ENSG00000230514 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000015452 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Xie J, Méndez JD, Méndez-Valenzuela V, Aguilar-Hernández MM (November 2013). "Cellular signalling of the receptor for advanced glycation end products (RAGE)". Cellular Signalling. 25 (11): 2185–2197. doi:10.1016/j.cellsig.2013.06.013. PMID 23838007.
  6. ^ Neeper M, Schmidt AM, Brett J, Yan SD, Wang F, Pan YC, et al. (July 1992). "Cloning and expression of a cell surface receptor for advanced glycosylation end products of proteins". The Journal of Biological Chemistry. 267 (21): 14998–15004. doi:10.1016/S0021-9258(18)42138-2. PMID 1378843.
  7. ^ Bierhaus A, Schiekofer S, Schwaninger M, Andrassy M, Humpert PM, Chen J, et al. (December 2001). "Diabetes-associated sustained activation of the transcription factor nuclear factor-kappaB". Diabetes. 50 (12): 2792–2808. doi:10.2337/diabetes.50.12.2792. PMID 11723063.
  8. ^ Gasparotto J, Girardi CS, Somensi N, Ribeiro CT, Moreira JC, Michels M, et al. (January 2018). "Receptor for advanced glycation end products mediates sepsis-triggered amyloid-β accumulation, Tau phosphorylation, and cognitive impairment". The Journal of Biological Chemistry. 293 (1): 226–244. doi:10.1074/jbc.M117.786756. PMC 5766916. PMID 29127203.
  9. ^ Hudson BI, Stickland MH, Futers TS, Grant PJ (June 2001). "Effects of novel polymorphisms in the RAGE gene on transcriptional regulation and their association with diabetic retinopathy". Diabetes. 50 (6): 1505–1511. doi:10.2337/diabetes.50.6.1505. PMID 11375354.
  10. ^ Hudson BI, Hofman MA, Bucciarelli L, Wendt T, Moser B, Lu Y, et al. (2002). "Glycation and diabetes: The RAGE connection" (PDF). Current Science. 83 (12): 1515–1521.
  11. ^ a b c Oczypok EA, Perkins TN, Oury TD (June 2017). "All the "RAGE" in lung disease: The receptor for advanced glycation endproducts (RAGE) is a major mediator of pulmonary inflammatory responses". Paediatric Respiratory Reviews. 23: 40–49. doi:10.1016/j.prrv.2017.03.012. PMC 5509466. PMID 28416135.
  12. ^ Ibrahim ZA, Armour CL, Phipps S, Sukkar MB (December 2013). "RAGE and TLRs: relatives, friends or neighbours?". Molecular Immunology. 56 (4): 739–744. doi:10.1016/j.molimm.2013.07.008. PMID 23954397.
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  14. ^ Penumutchu SR, Chou RH, Yu C (November 2014). "Interaction between S100P and the anti-allergy drug cromolyn". Biochemical and Biophysical Research Communications. 454 (3): 404–409. doi:10.1016/j.bbrc.2014.10.048. PMID 25450399.
  15. ^ 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): 184–197. doi:10.1016/j.yexcr.2005.10.013. PMID 16297907.
  16. ^ Dahlmann M, Okhrimenko A, Marcinkowski P, Osterland M, Herrmann P, Smith J, et al. (May 2014). "RAGE mediates S100A4-induced cell motility via MAPK/ERK and hypoxia signaling and is a prognostic biomarker for human colorectal cancer metastasis". Oncotarget. 5 (10): 3220–3233. doi:10.18632/oncotarget.1908. PMC 4102805. PMID 24952599.
  17. ^ Hofmann MA, Drury S, Fu C, Qu W, Taguchi A, Lu Y, et al. (June 1999). "RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides". Cell. 97 (7): 889–901. doi:10.1016/S0092-8674(00)80801-6. PMID 10399917.
  18. ^ Hofmann MA, Drury S, Fu C, Qu W, Taguchi A, Lu Y, et al. (June 1999). "RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides". Cell. 97 (7): 889–901. doi:10.1016/S0092-8674(00)80801-6. PMID 10399917.
  19. ^ Hofmann MA, Drury S, Fu C, Qu W, Taguchi A, Lu Y, et al. (June 1999). "RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides". Cell. 97 (7): 889–901. doi:10.1016/S0092-8674(00)80801-6. PMID 10399917.
  20. ^ Hofmann MA, Drury S, Fu C, Qu W, Taguchi A, Lu Y, et al. (June 1999). "RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides". Cell. 97 (7): 889–901. doi:10.1016/S0092-8674(00)80801-6. PMID 10399917.
  21. ^ Gasparotto J, Ribeiro CT, da Rosa-Silva HT, Bortolin RC, Rabelo TK, Peixoto DO, et al. (May 2019). "Systemic Inflammation Changes the Site of RAGE Expression from Endothelial Cells to Neurons in Different Brain Areas". Molecular Neurobiology. 56 (5): 3079–3089. doi:10.1007/s12035-018-1291-6. hdl:11323/1858. PMID 30094805. S2CID 51953478.
  22. ^ Yammani RR (April 2012). "S100 proteins in cartilage: role in arthritis". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1822 (4): 600–606. doi:10.1016/j.bbadis.2012.01.006. PMC 3294013. PMID 22266138.
  23. ^ Kipfmueller F, Heindel K, Geipel A, Berg C, Bartmann P, Reutter H, et al. (June 2019). "Expression of soluble receptor for advanced glycation end products is associated with disease severity in congenital diaphragmatic hernia". American Journal of Physiology. Lung Cellular and Molecular Physiology. 316 (6): L1061–L1069. doi:10.1152/ajplung.00359.2018. PMID 30838867.
  24. ^ Kuroiwa Y, Takakusagi Y, Kusayanagi T, Kuramochi K, Imai T, Hirayama T, et al. (May 2013). "Identification and characterization of the direct interaction between methotrexate (MTX) and high-mobility group box 1 (HMGB1) protein". PLOS ONE. 8 (5): e63073. Bibcode:2013PLoSO...863073K. doi:10.1371/journal.pone.0063073. PMC 3643934. PMID 23658798.
  25. ^ 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): 532–534. doi:10.1016/j.ijcard.2013.01.002. PMID 23398829.
  26. ^ Dwir D, Giangreco B, Xin L, Tenenbaum L, Cabungcal JH, Steullet P, et al. (November 2020). "MMP9/RAGE pathway overactivation mediates redox dysregulation and neuroinflammation, leading to inhibitory/excitatory imbalance: a reverse translation study in schizophrenia patients". Molecular Psychiatry. 25 (11): 2889–2904. doi:10.1038/s41380-019-0393-5. hdl:11343/252888. PMC 7577857. PMID 30911107.
  27. ^ Queisser MA, Kouri FM, Königshoff M, Wygrecka M, Schubert U, Eickelberg O, et al. (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): 337–345. doi:10.1165/rcmb.2007-0244OC. PMID 18421017.
  28. ^ Egaña-Gorroño L, López-Díez R, Yepuri G, Ramirez LS, Reverdatto S, Gugger PF, et al. (2020-03-10). "Receptor for Advanced Glycation End Products (RAGE) and Mechanisms and Therapeutic Opportunities in Diabetes and Cardiovascular Disease: Insights From Human Subjects and Animal Models". Frontiers in Cardiovascular Medicine. 7: 37. doi:10.3389/fcvm.2020.00037. PMC 7076074. PMID 32211423.
  29. ^ Ramasamy R, Shekhtman A, Schmidt AM (2016-04-02). "The multiple faces of RAGE--opportunities for therapeutic intervention in aging and chronic disease". Expert Opinion on Therapeutic Targets. 20 (4): 431–446. doi:10.1517/14728222.2016.1111873. PMC 4941230. PMID 26558318.
  30. ^ Egaña-Gorroño L, López-Díez R, Yepuri G, Ramirez LS, Reverdatto S, Gugger PF, et al. (2020-03-10). "Receptor for Advanced Glycation End Products (RAGE) and Mechanisms and Therapeutic Opportunities in Diabetes and Cardiovascular Disease: Insights From Human Subjects and Animal Models". Frontiers in Cardiovascular Medicine. 7: 37. doi:10.3389/fcvm.2020.00037. PMC 7076074. PMID 32211423.
  31. ^ Egaña-Gorroño L, López-Díez R, Yepuri G, Ramirez LS, Reverdatto S, Gugger PF, et al. (2020-03-10). "Receptor for Advanced Glycation End Products (RAGE) and Mechanisms and Therapeutic Opportunities in Diabetes and Cardiovascular Disease: Insights From Human Subjects and Animal Models". Frontiers in Cardiovascular Medicine. 7: 37. doi:10.3389/fcvm.2020.00037. PMC 7076074. PMID 32211423.
  32. ^ Egaña-Gorroño L, López-Díez R, Yepuri G, Ramirez LS, Reverdatto S, Gugger PF, et al. (2020-03-10). "Receptor for Advanced Glycation End Products (RAGE) and Mechanisms and Therapeutic Opportunities in Diabetes and Cardiovascular Disease: Insights From Human Subjects and Animal Models". Frontiers in Cardiovascular Medicine. 7: 37. doi:10.3389/fcvm.2020.00037. PMC 7076074. PMID 32211423.
  33. ^ Egaña-Gorroño L, López-Díez R, Yepuri G, Ramirez LS, Reverdatto S, Gugger PF, et al. (2020-03-10). "Receptor for Advanced Glycation End Products (RAGE) and Mechanisms and Therapeutic Opportunities in Diabetes and Cardiovascular Disease: Insights From Human Subjects and Animal Models". Frontiers in Cardiovascular Medicine. 7: 37. doi:10.3389/fcvm.2020.00037. PMC 7076074. PMID 32211423.
  34. ^ Ramasamy R, Shekhtman A, Schmidt AM (2016-04-02). "The multiple faces of RAGE--opportunities for therapeutic intervention in aging and chronic disease". Expert Opinion on Therapeutic Targets. 20 (4): 431–446. doi:10.1517/14728222.2016.1111873. PMC 4941230. PMID 26558318.
  35. ^ Ramasamy R, Shekhtman A, Schmidt AM (2016-04-02). "The multiple faces of RAGE--opportunities for therapeutic intervention in aging and chronic disease". Expert Opinion on Therapeutic Targets. 20 (4): 431–446. doi:10.1517/14728222.2016.1111873. PMC 4941230. PMID 26558318.
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  37. ^ Han YT, Choi GI, Son D, Kim NJ, Yun H, Lee S, et al. (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): 9120–9135. doi:10.1021/jm300172z. PMID 22742537.
  38. ^ Han YT, Kim K, Choi GI, An H, Son D, Kim H, et al. (May 2014). "Pyrazole-5-carboxamides, novel inhibitors of receptor for advanced glycation end products (RAGE)". European Journal of Medicinal Chemistry. 79: 128–142. doi:10.1016/j.ejmech.2014.03.072. PMID 24727489.
  39. ^ Han YT, Kim K, Son D, An H, Kim H, Lee J, et al. (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): 579–587. doi:10.1016/j.bmc.2014.12.003. PMID 25533401.
  40. ^ "Azeliragon". vTv Therapeutics. Retrieved 23 July 2015.
  41. ^ 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
  42. ^ vTv Halts Trials of Alzheimer's Candidate Azeliragon after Phase III Failure Apr 2018

Further reading

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