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.
Highlights
The endothelial Angiopoietin-Tie[2] ligand-receptor system has been recognized as a non-redundant signalling pathway that controls vascular inflammation and permeability, key features of early acute kidney injury (AKI)
Given the absence of redundant systems to bypass the function of Tie[2], it was speculated that exogenous repletion of Angpt[1] rescues Tie[2] signalling and effectively abolishes microvascular leakage in ischemia-reperfusion injury (IRI)
In this study we tested the effects of the novel Tie2-agonist tetrameric peptide, Vasculotide (VT)[23,24] in a murine model of renal IRI
Summary
The endothelial Angiopoietin-Tie[2] ligand-receptor system has been recognized as a non-redundant signalling pathway that controls vascular inflammation and permeability, key features of early AKI. Release of Angiopoietin-2 (Angpt2) from endothelial Weibel-Pallade bodies disrupts the constitutive Angpt1-Tie[2] signaling by preventing Angpt[1] from binding to the receptor[13,14] thereby promoting inflammation and permeability[15,16,17]. Given the absence of redundant systems to bypass the function of Tie[2], it was speculated that exogenous repletion of Angpt[1] rescues Tie[2] signalling and effectively abolishes microvascular leakage in ischemia-reperfusion injury (IRI). In this study we tested the effects of the novel Tie2-agonist tetrameric peptide, Vasculotide (VT)[23,24] in a murine model of renal IRI
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