This application responds to FOA PAR-13-114, Improvement of Animal Models for Stem Cell-Based Regenerative Medicine, which encourages R01 applications aimed at characterizing animal stem cells and improving existing, and creating new, animal models for human disease. The intent of that initiative is to facilitate the use of stem cell-based therapies for regenerative medicine, including demonstration of the functionality of specific stem cells or their derivatives and their effectiveness in improved anima models. The metabolic syndrome (MetS) is a constellation of cardiovascular risk factors, which induces kidney damage and raises the risk for chronic kidney disease, partly by rendering it vulnerable to ischemia. Indeed, MetS co- existing with renovascular disease (RVD) is linked to poorer outcomes after revascularization, possibly due to inflammation that characterizes MetS. However, tools to blunt its renal effects are yet to be identified, partly due to the lack of translational animal models of MetS and clinically applicable therapeutic tools. Adipose tissue-derived Mesenchymal stem cells (MSC) have potent paracrine anti-inflammatory properties, which recent studies have attributed to extracellular microvesicles (EV) that they release. Yet, the efficacy of EV delivery has not been tested in a large animal model. The goal of the current proposal is to develop and evaluate the capability of this novel platform to improve kidney viability in a novel swine model of MetS and RVD that we recently developed which closely mimics human pathophysiology and allows translational studies and interventions relevant to human clinical medicine. The hypothesis underlying this project is that similar to their parent MSC, MSC-derived EV is distinct and effective in decreasing damage in the kidney in MetS complicated by unilateral RVD. We will initially characterize the mRNA and micro-RNA expression pattern of EV in comparison to their parent MSC, and then assess their effects after intra-renal injection. To this end we will employ cutting-edge physiologic imaging techniques that we developed and refined, which are uniquely suited for studying the single kidney, including computed tomography and magnetic resonance imaging. Moreover, we will study the mechanism by which EVs mediate the benefits conferred by their parent MSC.
Three specific aims will be pursued:
Specific Aim 1 will test the hypothesis that MSC-derived EV show distinct patterns of mRNA and micro-RNA expression, which include enrichment with pro-angiogenic cargo.
Specific Aim 2 will test the hypothesis that EV will attenuate injury of MetS-RVD kidneys.
Specific Aim 3 will test the hypothesis that EVs mediate the paracrine angiogenic effects of their parent MSC via delta-like-4 signaling. The novel tools developed and employed in the proposed studies provide a unique opportunity to assess the feasibility of modifying renal outcomes in MetS/RVD using innovative and clinically applicable interventions and treatment platforms, which will likely contribute towards management strategies for patients with RVD & MetS.

Public Health Relevance

Developing adequate management strategies for chronic kidney injury associated with the metabolic syndrome (including obesity, elevated glucose, cholesterol, and blood pressure), presents a major challenge for healthcare professionals. The use of membrane microparticles derived from adipose tissue-derived mesenchymal stem cells is a novel experimental strategy to blunt kidney damage, which is yet to be attempted in clinically applicable models of the metabolic syndrome or renovascular disease. The proposed studies may establish this novel, clinically feasible therapeutic strategy and will likely contribute significantly towards management of patients with this disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK102325-01A1
Application #
8882834
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Flessner, Michael Francis
Project Start
2015-03-10
Project End
2019-02-28
Budget Start
2015-03-10
Budget End
2016-02-29
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
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Zhu, Xiang-Yang; Ma, Shuangtao; Eirin, Alfonso et al. (2016) Functional Plasticity of Adipose-Derived Stromal Cells During Development of Obesity. Stem Cells Transl Med 5:893-900
Kwon, Soon Hyo; Woollard, John R; Saad, Ahmed et al. (2016) Elevated urinary podocyte-derived extracellular microvesicles in renovascular hypertensive patients. Nephrol Dial Transplant :
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Eirin, Alfonso; Saad, Ahmed; Tang, Hui et al. (2016) Urinary Mitochondrial DNA Copy Number Identifies Chronic Renal Injury in Hypertensive Patients. Hypertension 68:401-10
Sun, Dong; Eirin, Alfonso; Ebrahimi, Behzad et al. (2016) Early atherosclerosis aggravates renal microvascular loss and fibrosis in swine renal artery stenosis. J Am Soc Hypertens 10:325-35
Eirin, Alfonso; Zhu, Xiang-Yang; Puranik, Amrutesh S et al. (2016) Comparative proteomic analysis of extracellular vesicles isolated from porcine adipose tissue-derived mesenchymal stem/stromal cells. Sci Rep 6:36120
Lerman, Lilach O; Textor, Stephen C (2016) Hypertension in 2015: Resistant hypertension: impact and evolving treatment options. Nat Rev Nephrol 12:70-2
Zhang, Xin; Krier, James D; Amador Carrascal, Carolina et al. (2016) Low-Energy Shockwave Therapy Improves Ischemic Kidney Microcirculation. J Am Soc Nephrol 27:3715-3724

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