Renal Therapeutic Angiogenesis Using a Bioengineered Polymer-Stabilized Vascular Endothelial Growth Factor Construct.

Autor:	Chade AR; Department of Physiology and Biophysics, Department of Medicine, Department of Radiology, achade@umc.edu., Tullos NA; Department of Physiology and Biophysics., Harvey TW; Department of Physiology and Biophysics., Mahdi F; Department of Neurology, and., Bidwell GL 3rd; Department of Neurology, and Department of Biochemistry, University of Mississippi Medical Center, Jackson, Mississippi.
Jazyk:	angličtina
Zdroj:	Journal of the American Society of Nephrology : JASN [J Am Soc Nephrol] 2016 Jun; Vol. 27 (6), pp. 1741-52. Date of Electronic Publication: 2015 Nov 05.
DOI:	10.1681/ASN.2015040346
Abstrakt:	Renovascular disease (RVD) induces renal microvascular (MV) rarefaction that drives progressive kidney injury. In previous studies, we showed that renal vascular endothelial growth factor (VEGF) therapy attenuated MV damage, but did not resolve renal injury at practical clinical doses. To increase the bioavailability of VEGF, we developed a biopolymer-stabilized elastin-like polypeptide (ELP)-VEGF fusion protein and determined its in vivo potential for therapeutic renal angiogenesis in RVD using an established swine model of chronic RVD. We measured single-kidney blood flow (RBF) and GFR and established the degree of renal damage after 6 weeks of RVD. Pigs then received a single stenotic kidney infusion of ELP-VEGF (100 μg/kg), a matching concentration of unconjugated VEGF (18.65 μg/kg), ELP alone (100 μg/kg), or placebo. Analysis of organ distribution showed high renal binding of ELP-VEGF 4 hours after stenotic kidney infusion. Therapeutic efficacy was determined 4 weeks after infusion. ELP-VEGF therapy improved renal protein expression attenuated in RVD, restoring expression levels of VEGF, VEGF receptor Flk-1, and downstream angiogenic mediators, including phosphorylated Akt and angiopoietin-1 and -2. This effect was accompanied by restored MV density, attenuated fibrogenic activity, and improvements in RBF and GFR greater than those observed with placebo, ELP alone, or unconjugated VEGF. In summary, we demonstrated the feasibility of a novel therapy to curtail renal injury. Recovery of the stenotic kidney in RVD after ELP-VEGF therapy may be driven by restoration of renal angiogenic signaling and attenuated fibrogenic activity, which ameliorates MV rarefaction and improves renal function. (Copyright © 2016 by the American Society of Nephrology.)
Databáze:	MEDLINE
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