AgeR deletion decreases soluble fms-like tyrosine kinase 1 production and improves post-ischemic angiogenesis in uremic mice

• Published in: Angiogenesis (London) Vol. 24; no. 1; pp. 47 - 55
• Main Authors: Dupont, Vincent, Al-Rifai, Rida, Poitevin, Gael, Ortillon, Jeremy, Jayyosi, Laura, Terryn, Christine, Francois, Caroline, Rieu, Philippe, Fritz, Günter, Boulagnon-Rombi, Camile, Fichel, Caroline, Schmidt, Ann Marie, Tournois, Claire, Nguyen, Philippe, Touré, Fatouma
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 01.02.2021; Springer Nature B.V; Springer Verlag
• Subjects: Advanced glycosylation end products; Angiogenesis; Animals; Antiangiogenics; Biochemistry; Biochemistry, Molecular Biology; Biomarkers - blood; Biomedical and Life Sciences; Biomedicine; Brief Communication; Cancer Research; Cardiology; Cell Biology; Cell Line; Deletion; Density; Femoral artery; Flexible manufacturing systems; Gene Deletion; Glycosylation; Human health and pathology; Humans; Imagery; Ischemia; Ischemia - complications; Kidney diseases; Kinases; Life Sciences; Ligands; Male; Mice; Mice, Inbred C57BL; Neovascularization, Physiologic; Nephrectomy; Oncology; Ophthalmology; Protein-tyrosine kinase; Receptor for Advanced Glycation End Products - deficiency; Receptor for Advanced Glycation End Products - metabolism; Recovery of function; Reperfusion; Ribonucleic acid; RNA; RNA - metabolism; Solubility; Tyrosine; Up-Regulation; Uremia; Uremia - complications; Vascular diseases; Vascular Endothelial Growth Factor Receptor-1 - biosynthesis; Angiogenesis; Soluble fms-like tyrosine kinase 1; Chronic kidney disease; Receptor for advanced glycation end products; Ischemia–reperfusion
• ISSN: 0969-6970; 1573-7209
• DOI: 10.1007/s10456-020-09747-5

Peripheral arterial disease occurs more frequently and has a worse prognosis in patients with chronic kidney disease (CKD). The receptor for advanced glycation end products (RAGE) is involved in multiple aspects of uremia-associated vasculopathy. Previous data suggest that the RAGE pathway may promote soluble fms-like tyrosine kinase 1 (sFlt1) production, an anti-angiogenic molecule. Thus, we tested the hypothesis that the deletion of AgeR would decrease sFlt1 production and improve post-ischemic revascularization in uremic condition. We used a well-established CKD model (5/6 nephrectomy) in WT and AgeR −/− C57/Bl6 mice. Hindlimb ischemia was induced by femoral artery ligation. Revascularization was evaluated by complementary approaches: ischemic limb retraction, LASCA imagery, and capillary density. The production of sFlt1 was assessed at both RNA and protein levels. After hindlimb ischemia, uremic mice showed slower functional recovery ( p  < 0.01), decreased reperfusion ( p  < 0.01), lower capillary density ( p  = 0.02), and increased circulating sFlt1 levels ( p  = 0.03). AgeR deletion restored post-ischemic angiogenesis and was protective from sFlt1 increase in uremic mice. These findings show the main role of RAGE in post-ischemic angiogenesis impairment associated with CKD. RAGE may represent a key target for building new therapeutic approaches to improve the outcome of CKD patients with PAD.