title: The Synthetic Tie2 Agonist Peptide Vasculotide Protects Renal Vascular Barrier Function In Experimental Acute Kidney Injury.
abstract: 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 < 0.05]. VT is inexpensive to produce, chemically stable and unrelated to any Tie2 ligands. Thus, VT may represent a novel therapy to prevent AKI in patients.
authors.affiliation: Department of Medicine D, Division of General Internal Medicine, Nephrology, and Rheumatology, University Hospital Münster, Albert-Schweitzer-Strasse 33, 48149 Münster, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Rübig
authors.affiliation: Department of Cardiology, University Hospital Münster, Albert-Schweitzer-Strasse 33, 48149 Münster, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Stypmann
authors.affiliation: Vasomune Therapeutics, 661 University Avenue Suite 465, Toronto, Ontario, Canada.
authors.forename: Paul
authors.initials: P
authors.lastname: Van Slyke
authors.affiliation: Molecular and Cellular Biology Research, Sunnybrook Research Institute, and Department of Medical Biophysics, University of Toronto, Ontario, Canada.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Dumont
authors.affiliation: Institute of Pathology at St Franziskus Hospital Münster, Hohenzollernring 64, 48145 Münster, Germany.
authors.forename: Tilmann
authors.initials: T
authors.lastname: Spieker
authors.affiliation: Department of Medicine D, Division of General Internal Medicine, Nephrology, and Rheumatology, University Hospital Münster, Albert-Schweitzer-Strasse 33, 48149 Münster, Germany.
authors.forename: Konrad
authors.initials: K
authors.lastname: Buscher
authors.affiliation: Department of Medicine D, Division of General Internal Medicine, Nephrology, and Rheumatology, University Hospital Münster, Albert-Schweitzer-Strasse 33, 48149 Münster, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Reuter
authors.affiliation: Department of Dermatology, University Hospital Münster, Von-Esmarch-Straße 58, 48149 Münster, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Goerge
authors.affiliation: Department of Medicine D, Division of General Internal Medicine, Nephrology, and Rheumatology, University Hospital Münster, Albert-Schweitzer-Strasse 33, 48149 Münster, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Pavenstädt
authors.affiliation: Department of Medicine D, Division of General Internal Medicine, Nephrology, and Rheumatology, University Hospital Münster, Albert-Schweitzer-Strasse 33, 48149 Münster, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Kümpers
mesh_terms: D058186:Acute Kidney Injury / Q000473:pathology / Q000517:prevention & control*; D000418:Albumins / Q000378:metabolism; D042683:Angiopoietin-1 / Q000737:chemistry; D000818:Animals; D040761:Biomimetic Materials / Q000737:chemistry; D002199:Capillary Permeability / Q000187:drug effects; D003404:Creatinine / Q000097:blood; D007668:Kidney / Q000098:blood supply / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D010446:Peptide Fragments / Q000737:chemistry / Q000627:therapeutic use*; D042787:Receptor, TIE-2 / Q000819:agonists*; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*
chemical_list: D000418:Albumins; D042683:Angiopoietin-1; D010446:Peptide Fragments; C000613371:Vasculotide; D003404:Creatinine; D042787:Receptor, TIE-2; C079086:Tek protein, mouse