Renal injury in atherosclerotic renovascular disease (RVD) often progresses despite restoring large vessel patency. This process is linked to rarefaction of microvessels, cortical hypoxia, stimulation of inflammatory cytokines and recruitment of progenitor and inflammatory cells. Our overall hypothesis is that the severity of renal injury and recovery in human RVD will depend upon not only restoration of blood flow but also a transition from a pro-inflammatory, fibrogenic phenotype to one favorable to restoring tubular integrity that will reflect the functional balance of M1 (inflammatory) and M2 (reparative) macrophages.
The specific aims i n this project apply novel technologies to define cortical and medullary blood flow and oxygenation in human subjects. They will be combined with studies of kidney biopsies and renal venous cytokine patterns that can be ascribed to M1 or M2 macrophages. We propose to modify the inflammatory and angiogenic pathways by delivering intra-renal autologous adipose-derived mesenchymal stem cells (MSCs) capable of immunomodulation.
Specific Aim 1 will define the relationship between cortical and medullary blood flows, tissue hypoxia, and inflammatory signals, defined by trans-renal cytokine gradients in RVD. Our hypothesis is that the level of cortical hypoxia (defined both by blood flow reduction and elevated deoxyhemoglobin) will be related to induction of inflammatory homing signals.
Specific Aim 2 will undertake to modify the intrarenal microenvironment by delivery of autologous adipose-derived MSCs in advanced RVD. The hypothesis to be tested is that MSCs will result in measurable increases in glomerular filtration, cortical and medullary blood flow and oxygenation, and reduced tissue inflammation with a cytokine signature characteristic of M2 macrophages.
Specific Aim 3 will combine administration of MSC's to individuals with advanced RVD undergoing renal revascularization via renal artery stenting. Our hypothesis is that MSCs combined with renal artery stenting will augment tissue repair and will better restore kidney oxygenation and function than MSCs alone. These studies will provide the first investigation in humans of the potential for cell-based therapy to augment vascular and functional repair after restoring blood flow to the kidney.

Public Health Relevance

These studies are relevant to prevention of progressive kidney disease, particularly in older subjects with widespread vascular disease. They will address directly evolving concepts linking large-vessel occlusive disease to inflammatory renal injury. Importantly, these studies will for the first time explore the role of mesenchymal stem cells as a means to repair tissue injury beyond an occlusive vascular lesion in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK100081-01A1
Application #
8722682
Study Section
Special Emphasis Panel (ZRG1-DKUS-A (05))
Program Officer
Flessner, Michael Francis
Project Start
2014-05-20
Project End
2019-04-30
Budget Start
2014-05-20
Budget End
2015-04-30
Support Year
1
Fiscal Year
2014
Total Cost
$569,367
Indirect Cost
$193,118
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Saad, Ahmed; Zhu, Xiang-Yang; Herrmann, Sandra et al. (2016) Adipose-derived mesenchymal stem cells from patients with atherosclerotic renovascular disease have increased DNA damage and reduced angiogenesis that can be modified by hypoxia. Stem Cell Res Ther 7:128
Textor, Stephen C; McKusick, Michael M (2016) Renal artery stenosis: if and when to intervene. Curr Opin Nephrol Hypertens 25:144-51
Reriani, Martin; Sara, Jaskanwal D; Flammer, Andreas J et al. (2016) Coronary endothelial function testing provides superior discrimination compared with standard clinical risk scoring in prediction of cardiovascular events. Coron Artery Dis 27:213-20
Hickson, LaTonya J; Eirin, Alfonso; Lerman, Lilach O (2016) Challenges and opportunities for stem cell therapy in patients with chronic kidney disease. Kidney Int 89:767-78
Herrmann, Sandra M S; Saad, Ahmed; Eirin, Alfonso et al. (2016) Differences in GFR and Tissue Oxygenation, and Interactions between Stenotic and Contralateral Kidneys in Unilateral Atherosclerotic Renovascular Disease. Clin J Am Soc Nephrol 11:458-69
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
Lerman, Lilach O; Textor, Stephen C (2016) Hypertension in 2015: Resistant hypertension: impact and evolving treatment options. Nat Rev Nephrol 12:70-2
Saad, Ahmed; Wang, Wei; Herrmann, Sandra M S et al. (2016) Atherosclerotic renal artery stenosis is associated with elevated cell cycle arrest markers related to reduced renal blood flow and postcontrast hypoxia. Nephrol Dial Transplant 31:1855-1863
Kwon, Soon Hyo; Tang, Hui; Saad, Ahmed et al. (2016) Differential Expression of microRNAs in Urinary Extracellular Vesicles Obtained From Hypertensive Patients. Am J Kidney Dis 68:331-2

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