The Synthetic Tie2 Agonist Peptide Vasculotide Protects Renal Vascular Barrier Function In Experimental Acute Kidney Injury

• Published in: Scientific reports 2016-02, Vol.6 (1), p.22111-22111, Article 22111
• Main Authors: Rübig, Eva, Stypmann, Jörg, Van Slyke, Paul, Dumont, Daniel J, Spieker, Tilmann, Buscher, Konrad, Reuter, Stefan, Goerge, Tobias, Pavenstädt, Hermann, Kümpers, Philipp
• Format: Article
• Language: English
• Subjects: 631/154/556; 692/308/153; 692/699/1585/4; 82/51; 82/80; 96/95; Acute Kidney Injury - pathology; Acute Kidney Injury - prevention & control; Albumin; Albumins - metabolism; Angiopoietin; Angiopoietin-1 - chemistry; Animal models; Animals; Biomimetic Materials - chemistry; Blood flow; Cadherins; Capillary Permeability - drug effects; Cell activation; Creatinine; Creatinine - blood; Cysteine; Edema; Humanities and Social Sciences; Ischemia; Kidney - blood supply; Kidney - drug effects; Kidneys; Ligands; Male; Mice; Mice, Inbred C57BL; Microvasculature; Models, Animal; multidisciplinary; Nitrogen; Peptide Fragments - chemistry; Peptide Fragments - therapeutic use; Polyethylene glycol; Receptor, TIE-2 - agonists; Renal artery; Renal function; Reperfusion; Reperfusion Injury - pathology; Reperfusion Injury - prevention & control; Rodents; Science; Urea
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep22111

Microvascular barrier dysfunction plays a major role in the pathophysiology of acute kidney injury (AKI). Angiopoietin-1, the natural agonist ligand for the endothelial-specific Tie2 receptor, is a non-redundant endothelial survival and vascular stabilization factor. Here we evaluate the efficacy of a polyethylene glycol-clustered Tie2 agonist peptide, vasculotide (VT), to protect against endothelial-cell activation with subsequent microvascular dysfunction in a murine model of ischemic AKI. Renal ischemia reperfusion injury (IRI) was induced by clamping of the renal arteries for 35 minutes. Mice were treated with VT or PEGylated cysteine before IRI. Sham-operated animals served as time-matched controls. Treatment with VT significantly reduced transcapillary albumin flux and renal tissue edema after IRI. The protective effects of VT were associated with activation of Tie2 and stabilization of its downstream effector, VE-cadherin in renal vasculature. VT abolished the decline in renal tissue blood flow, attenuated the increase of serum creatinine and blood urea nitrogen after IRI, improved recovery of renal function and markedly reduced mortality compared to PEG [HR 0.14 (95% CI 0.05–0.78) P