title: Effect of chronic hypoxia on RAGE and its soluble forms in lungs and plasma of mice.
abstract: The receptor for advanced glycation end products (RAGE) is a multi-ligand receptor. Alternative splicing and enzymatic shedding produce soluble forms that protect against damage by ligands including Advanced Glycation End products (AGEs). A link between RAGE and oxygen levels is evident from studies showing RAGE-mediated injury following hyperoxia. The effect of hypoxia on pulmonary RAGE expression and circulating sRAGE levels is however unknown. Therefore mice were exposed to chronic hypoxia for 21 d and expression of RAGE, sheddases in lungs and circulating sRAGE were determined. In addition, accumulation of AGEs in lungs and expression of the AGE detoxifying enzyme GLO1 and receptors were evaluated. In lung tissue gene expression of total RAGE, variants 1 and 3 were elevated in mice exposed to hypoxia, whereas mRAGE and sRAGE protein levels were decreased. In the hypoxic group plasma sRAGE levels were enhanced. Although the levels of pro-ADAM10 were elevated in lungs of hypoxia exposed mice, the relative amount of the active form was decreased and gelatinase activity unaffected. In the lungs, the RAGE ligand HMGB1 was decreased and of the AGEs, only LW-1 was increased by chronic hypoxia. Gene expression of AGE receptors 2 and 3 was significantly upregulated. Chronic hypoxia is associated with downregulation of pulmonary RAGE protein levels, but a relative increase in sRAGE. These alterations might be part of the adaptive and protective response mechanism to chronic hypoxia and are not associated with AGE formation except for the fluorophore LW-1 which emerges as a novel marker of tissue hypoxia.
authors.affiliation: Department of Respiratory Medicine, Maastricht University, Maastricht, The Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: Gopal
authors.affiliation: Department of Respiratory Medicine, Maastricht University, Maastricht, The Netherlands.
authors.forename: H R
authors.initials: HR
authors.lastname: Gosker
authors.affiliation: Department of Respiratory Medicine, Maastricht University, Maastricht, The Netherlands.
authors.forename: C C de
authors.initials: CC
authors.lastname: Theije
authors.affiliation: Department of Respiratory Medicine, Maastricht University, Maastricht, The Netherlands.
authors.forename: I M
authors.initials: IM
authors.lastname: Eurlings
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: D R
authors.initials: DR
authors.lastname: Sell
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: V M
authors.initials: VM
authors.lastname: Monnier
authors.affiliation: Department of Respiratory Medicine, Maastricht University, Maastricht, The Netherlands. Electronic address: n.reynaert@maastrichtuniversity.nl.
authors.forename: N L
authors.initials: NL
authors.lastname: Reynaert
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002908:Chronic Disease; D015870:Gene Expression; D017127:Glycation End Products, Advanced / Q000378:metabolism; D024243:HMGB1 Protein / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007791:Lactoylglutathione Lyase / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012995:Solubility; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D017127:Glycation End Products, Advanced; D024243:HMGB1 Protein; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008565:Membrane Proteins; D020033:Protein Isoforms; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D042461:Vascular Endothelial Growth Factor A; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491234:Adam10 protein, mouse; D007791:Lactoylglutathione Lyase
keywords: AGEs; Detoxification; Hypoxia; RAGE expression; Shedding