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A BIOPOLYMER‐DELIVERED VEGF CONSTRUCT IMPROVES KIDNEY RECOVERY BY STIMULATING PROANGIOGENIC SIGNALING AND RENAL PROGENITOR CELL MOBILIZATION IN CHRONIC RENOVASCULAR DISEASE
Author(s) -
Guise Erika R.,
Harvey Taylor W.,
Williams Maxx L.,
Chade Alejandro R.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.1029.2
Subject(s) - medicine , kidney , kidney disease , progenitor cell , vascular endothelial growth factor , ex vivo , urology , fibrosis , renal function , pathology , endocrinology , in vivo , stem cell , biology , vegf receptors , microbiology and biotechnology
The evolving renal damage in chronic renovascular disease (RVD) is paralleled by a progressive renal microvascular (MV) rarefaction, which associates with decreased renal bioavailability of vascular endothelial growth factor (VEGF). We designed a novel bioengineered fusion of an elastin‐like polypeptide (ELP) carrier with VEGF that can improve renal function, decrease MV rarefaction, and reduce injury in RVD after a single administration. We aimed to elucidate the mechanisms of the long‐term renoprotection in RVD by ELP‐VEGF therapy. RVD was induced by unilateral renal artery stenosis in 14 pigs. Six weeks later, single‐kidney blood flow (RBF) and filtration (GFR) were quantified in vivo using multi‐detector CT, and then pigs were randomized to either placebo (RVD) or single IV administration of ELP‐VEGF (RVD+ELP‐VEGF IV). Pigs were observed for four additional weeks; in vivo CT studies repeated, then pigs were euthanized, and ex vivo renal MV micro‐CT quantification, MV remodeling, renal expression of pro‐angiogenic factors, and fibrosis were determined. Single IV administration of ELP‐VEGF improved stenotic‐kidney RBF, GFR, MV density and media‐to‐lumen ratio. These improvements were accompanied by restored stenotic‐kidney expression of VEGF, the Flk‐1 receptor, progenitor cell mobilization factors SDF‐1 and oct‐4, and attenuated fibrosis ( Figure). Our study describes the potential underlying mechanism of long‐term renal recovery after single ELP‐VEGF therapy. The stenotic‐kidney improvements were likely driven by restored VEGF signaling and subsequent stimulation of renal progenitor cells, which ultimately led to a sustained improvement of MV rarefaction, renal injury, and consequent recovery of renal hemodynamics and function. Support or Funding Information Support: NIH‐NHLBI (HL095638) and AHA (18490005)