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Updated: Apr 17, 2026
Induction and Characterization of Pulmonary Hypertension in Mice using the Hypoxia/SU5416 Model
Published on: June 3, 2020
Effect of chronic hypoxia on RAGE and its soluble forms in lungs and plasma of mice
P Gopal1, H R Gosker1, C C de Theije1
1Department of Respiratory Medicine, Maastricht University, Maastricht, The Netherlands.
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.
Insights
Chronic hypoxia decreases pulmonary receptor for advanced glycation end products (RAGE) protein but increases circulating soluble RAGE (sRAGE). These changes may protect against hypoxia, with LW-1 emerging as a novel hypoxia marker.
Area of Science:
- Pulmonary Medicine
- Molecular Biology
- Physiology
Background:
- Receptor for advanced glycation end products (RAGE) is a multi-ligand receptor involved in cellular responses.
- Soluble forms of RAGE (sRAGE) protect against RAGE ligand damage.
- RAGE is implicated in hyperoxia injury, but its role in hypoxia is unclear.
Purpose of the Study:
- To investigate the effect of chronic hypoxia on pulmonary RAGE expression and circulating sRAGE levels.
- To evaluate AGE accumulation and related enzyme/receptor expression under hypoxia.
- To understand RAGE pathway adaptations to chronic hypoxia in the lungs.
Main Methods:
- Mice were exposed to chronic hypoxia for 21 days.
- Expression of RAGE, sheddases, AGEs, GLO1, and AGE receptors in lung tissue and plasma were analyzed.
- Gene and protein expression levels were quantified.
Main Results:
- Hypoxia elevated gene expression of total RAGE and variants 1 and 3, but decreased RAGE and sRAGE protein levels in lung tissue.
- Plasma sRAGE levels were significantly enhanced in hypoxic mice.
- Lung HMGB1 levels decreased, while LW-1 (an AGE) increased; AGE receptors 2 and 3 were upregulated.
Conclusions:
- Chronic hypoxia downregulates pulmonary RAGE protein but increases circulating sRAGE, potentially as a protective adaptive mechanism.
- These RAGE pathway alterations are not linked to general AGE formation, except for LW-1.
- LW-1 emerges as a novel marker for tissue hypoxia.
