Endothelial outgrowth cells shift macrophage phenotype and improve kidney viability in swine renal artery stenosis

Alfonso Eirin, Xiang Yang Zhu, Zilun Li, Behzad Ebrahimi, Xin Zhang, Hui Tang, Michael J. Korsmo, Alejandro R. Chade, Joseph P. Grande, Christopher J. Ward, Robert D. Simari, Amir Lerman, Stephen C. Textor, Lilach O. Lerman

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

OBJECTIVE - : Endothelial outgrowth cells (EOC) decrease inflammation and improve endothelial repair. Inflammation aggravates kidney injury in renal artery stenosis (RAS), and may account for its persistence upon revascularization. We hypothesized that EOC would decrease inflammatory (M1) macrophages and improve renal recovery in RAS. APPROACH AND RESULTS - : Pigs with 10 weeks of RAS were studied 4 weeks after percutaneous transluminal renal angioplasty (PTRA+stenting) or sham, with or without adjunct intrarenal delivery of autologous EOC (10×10), and compared with similarly treated normal controls (n=7 each). Single-kidney function, microvascular and tissue remodeling, inflammation, oxidative stress, and fibrosis were evaluated. Four weeks after PTRA, EOC were engrafted in injected RAS-kidneys. Stenotic-kidney glomerular filtration rate was restored in RAS+EOC, RAS+PTRA, and RAS+PTRA+EOC pigs, whereas stenotic-kidney blood flow and angiogenesis were improved and fibrosis attenuated only in EOC-treated pigs. Furthermore, EOC increased cell proliferation and decreased the ratio of M1 (inflammatory)/M2 (reparative) macrophages, as well as circulating levels and stenotic-kidney release of inflammatory cytokines. Cultured-EOC released microvesicles in vitro and induced phenotypic switch (M1-to-M2) in cultured monocytes, which was inhibited by vascular endothelial growth factor blockade. Finally, a single intrarenal injection of rh-vascular endothelial growth factor (0.05 μg/kg) in 7 additional RAS pigs also restored M1/M2 ratio 4 weeks later. CONCLUSIONS - : Intrarenal infusion of EOC after PTRA induced a vascular endothelial growth factor-mediated attenuation in macrophages inflammatory phenotype, preserved microvascular architecture and function, and decreased inflammation and fibrosis in the stenotic kidney, suggesting a novel mechanism and therapeutic potential for adjunctive EOC delivery in experimental RAS to improve PTRA outcomes.

Original languageEnglish (US)
Pages (from-to)1006-1013
Number of pages8
JournalArteriosclerosis, thrombosis, and vascular biology
Volume33
Issue number5
DOIs
StatePublished - May 2013

Keywords

  • kidney hypertension
  • macrophages
  • progenitor cells
  • renal artery stenosis
  • revascularization

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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