Mesenchymal Stem Cells Improve Medullary Inflammation and Fibrosis after Revascularization of Swine Atherosclerotic Renal Artery Stenosis

Behzad Ebrahimi, Alfonso Eirin, Zilun Li, Xiang Yang Zhu, Xin Zhang, Amir Lerman, Stephen C Textor, Lilach O Lerman

Research output: Contribution to journalArticle

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Abstract

Atherosclerotic renal artery stenosis (ARAS) raises blood pressure and can reduce kidney function. Revascularization of the stenotic renal artery alone does not restore renal medullary structure and function. This study tested the hypothesis that addition of mesenchymal stem cells (MSC) to percutaneous transluminal renal angioplasty (PTRA) can restore stenotic-kidney medullary tubular transport function and attenuate its remodeling. Twenty-seven swine were divided into three ARAS (high-cholesterol diet and renal artery stenosis) and a normal control group. Six weeks after ARAS induction, two groups were treated with PTRA alone or PTRA supplemented with adipose-tissue-derived MSC (10×106 cells intra-renal). Multi-detector computed tomography and blood-oxygenation-level-dependent (BOLD) MRI studies were performed 4 weeks later to assess kidney hemodynamics and function, and tissue collected a few days later for histology and micro-CT imaging. PTRA effectively decreased blood pressure, yet medullary vascular density remained low. Addition of MSC improved medullary vascularization in ARAS+PTRA+MSC and increased angiogenic signaling, including protein expression of vascular endothelial growth-factor, its receptor (FLK-1), and hypoxia-inducible factor-1α. ARAS+PTRA+MSC also showed attenuated inflammation, although oxidative-stress remained elevated. BOLD-MRI indicated that MSC normalized oxygen-dependent tubular response to furosemide (-4.3±0.9, -0.1±0.4, -1.6±0.9 and -3.6±1.0 s-1 in Normal, ARAS, ARAS+PTRA and ARAS+PTRA+MSC, respectively, p<0.05), which correlated with a decrease in medullary tubular injury score (R2 = 0.33, p = 0.02). Therefore, adjunctive MSC delivery in addition to PTRA reduces inflammation, fibrogenesis and vascular remodeling, and restores oxygen-dependent tubular function in the stenotic-kidney medulla, although additional interventions might be required to reduce oxidative-stress. This study supports development of cell-based strategies for renal protection in ARAS.

Original languageEnglish (US)
Article numbere67474
JournalPLoS One
Volume8
Issue number7
DOIs
StatePublished - Jul 3 2013

Fingerprint

Renal Artery Obstruction
Stem cells
fibrosis
Mesenchymal Stromal Cells
arteries
stem cells
Fibrosis
Swine
inflammation
kidneys
Inflammation
Kidney
swine
Angioplasty
Oxidative stress
Oxygenation
Blood pressure
Magnetic resonance imaging
Multidetector computed tomography
Blood

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Mesenchymal Stem Cells Improve Medullary Inflammation and Fibrosis after Revascularization of Swine Atherosclerotic Renal Artery Stenosis. / Ebrahimi, Behzad; Eirin, Alfonso; Li, Zilun; Zhu, Xiang Yang; Zhang, Xin; Lerman, Amir; Textor, Stephen C; Lerman, Lilach O.

In: PLoS One, Vol. 8, No. 7, e67474, 03.07.2013.

Research output: Contribution to journalArticle

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AU - Zhu, Xiang Yang

AU - Zhang, Xin

AU - Lerman, Amir

AU - Textor, Stephen C

AU - Lerman, Lilach O

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