Effect of chronic hypoxia on RAGE and its soluble forms in lungs and plasma of mice

• Published in: Biochimica et biophysica acta Vol. 1852; no. 5; pp. 992 - 1000
• Main Authors: Gopal, P., Gosker, H.R., Theije, C.C. de, Eurlings, I.M., Sell, D.R., Monnier, V.M., Reynaert, N.L.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.05.2015
• Subjects: ADAM Proteins - genetics; ADAM Proteins - metabolism; ADAM10 Protein; AGEs; Amyloid Precursor Protein Secretases - genetics; Amyloid Precursor Protein Secretases - metabolism; Animals; Blotting, Western; Cell Line, Tumor; Chronic Disease; Detoxification; Gene Expression; Glycation End Products, Advanced - metabolism; HMGB1 Protein - metabolism; Humans; Hypoxia; Hypoxia - blood; Hypoxia - genetics; Hypoxia - metabolism; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Lactoylglutathione Lyase - genetics; Lactoylglutathione Lyase - metabolism; Lung - metabolism; Male; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice, Inbred C57BL; Protein Isoforms - genetics; Protein Isoforms - metabolism; RAGE expression; Receptor for Advanced Glycation End Products; Receptors, Immunologic - blood; Receptors, Immunologic - genetics; Receptors, Immunologic - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Shedding; Solubility; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; Shedding; Hypoxia; RAGE expression; AGEs; Detoxification
• ISSN: 0925-4439; 0006-3002; 1879-260X
• DOI: 10.1016/j.bbadis.2015.02.003

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 21d 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. •Decreased pulmonary mRAGE and sRAGE protein levels but increased the ratio of sRAGE to mRAGE•Enhanced plasma sRAGE levels•Decreased active ADAM10 levels•Decreased HMGB1 levels, and increased the AGE LW1 which could be a new biomarker of tissue hypoxia