The impact of vascular disease on morbidity and mortality is on the rise in the Western world. Atherosclerotic renal artery stenosis (ARAS), a common etiology of chronic kidney disease, amplifies deterioration of renal function and attenuates its recovery following intervention. However, the mechanisms leading to these grave outcomes are yet to be identified, partly due to the lack of techniques capable of studying the kidney distal to ARAS, and of suitable experimental models of ARAS. The hypothesis underlying this proposal is that atherosclerosis blunts the recovery of the stenotic ARAS kidney following intervention by impairing renal function and exacerbating oxidative stress, inflammation, and fibrosis, and that high-resolution computed tomography (CT) techniques would be useful to explore and characterize renal injury and response to revascularization. This hypothesis will be tested in a novel pig model of unilateral ARAS that we have developed and characterized, using unique imaging approaches that we have refined to study single-kidney function and structure. Electron beam CT (EBCT) will quantify in vivo, in the stenotic kidney of pigs undergoing percutaneous transluminal renal angioplasty, the reversibility of alterations in renal regional volume, perfusion, GFR, segmental tubular function, and response to challenge. Micro-CT will be subsequently used to assess in situ renal microvascular remodeling, a hallmark of atherosclerosis. The imaging studies will be correlated with in vitro studies of renal redox status, inflammation, and fibrosis. Furthermore, the impact of preexisting renal injury on the response to revascularization will be explored by superimposing ARAS on tubulointerstitial injury or glomerulosclerosis. The effect of attenuation of renal injury will be studied using chronic supplementation of statins, drugs that decrease oxidative stress, inflammation, and fibrosis, and might improve renal outcomes before as well as after intervention. Moreover, renal alterations will be correlated with renal recovery, and potential predictors of interventional success will be determined. The proposed studies may greatly advance our understanding of the pathogenesis of renal injury in ARAS, and assist in development of imaging strategies to detect injury markers and identify predictors of renal viability. Thus, these studies may contribute towards management of patients with renovascular disease. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK073608-02
Application #
7270040
Study Section
Medical Imaging Study Section (MEDI)
Program Officer
Rys-Sikora, Krystyna E
Project Start
2006-08-15
Project End
2010-05-31
Budget Start
2007-06-01
Budget End
2008-05-31
Support Year
2
Fiscal Year
2007
Total Cost
$294,601
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Eirin, Alfonso; Zhu, Xiang-Yang; Jonnada, Sreela et al. (2018) Mesenchymal Stem Cell-Derived Extracellular Vesicles Improve the Renal Microvasculature in Metabolic Renovascular Disease in Swine. Cell Transplant 27:1080-1095
Meng, Yu; Eirin, Alfonso; Zhu, Xiang-Yang et al. (2018) The metabolic syndrome alters the miRNA signature of porcine adipose tissue-derived mesenchymal stem cells. Cytometry A 93:93-103
Jiang, Kai; Tang, Hui; Mishra, Prasanna K et al. (2018) Measurement of Murine Single-Kidney Glomerular Filtration Rate Using Dynamic Contrast-Enhanced MRI. Magn Reson Med 79:2935-2943
Conley, Sabena M; Zhu, Xiang-Yang; Eirin, Alfonso et al. (2018) Metabolic syndrome alters expression of insulin signaling-related genes in swine mesenchymal stem cells. Gene 644:101-106
Jiang, Kai; Tang, Hui; Mishra, Prasanna K et al. (2018) A rapid T1 mapping method for assessment of murine kidney viability using dynamic manganese-enhanced magnetic resonance imaging. Magn Reson Med 80:190-199
Zhu, Xiang-Yang; Zou, Xiangyu; Mukherjee, Rahul et al. (2018) Targeted Imaging of Renal Fibrosis Using Antibody-Conjugated Gold Nanoparticles in Renal Artery Stenosis. Invest Radiol 53:623-628
Zou, Xiangyu; Jiang, Kai; Puranik, Amrutesh S et al. (2018) Targeting Murine Mesenchymal Stem Cells to Kidney Injury Molecule-1 Improves Their Therapeutic Efficacy in Chronic Ischemic Kidney Injury. Stem Cells Transl Med 7:394-403
Meng, Yu; Eirin, Alfonso; Zhu, Xiang-Yang et al. (2018) Obesity-induced mitochondrial dysfunction in porcine adipose tissue-derived mesenchymal stem cells. J Cell Physiol 233:5926-5936
Zhang, Xin; Zhu, Xiangyang; Ferguson, Christopher Martyn et al. (2018) Magnetic resonance elastography can monitor changes in medullary stiffness in response to treatment in the swine ischemic kidney. MAGMA 31:375-382
Ebrahimi, Behzad; Saad, Ahmed; Jiang, Kai et al. (2017) Renal Adiposity Confounds Quantitative Assessment of Markers of Renal Diffusion With MRI: A Proposed Correction Method. Invest Radiol 52:672-679

Showing the most recent 10 out of 165 publications