This application responds to FOA PA-14-046, Mentored Clinical Scientist Research Career Development Award (Parent K08), which provides support and protected time to individuals with a clinical doctoral degree for an intensive, supervised research career development experience in the fields of biomedical and behavioral research, including translational research. The metabolic syndrome (MetS) is a cluster of co-existing conditions including obesity and diabetes, important risk factors for chroni kidney disease and cardiovascular morbidity. Coexisting MetS and renal artery stenosis (MetS+RAS) intensify inflammation and lead to chronic kidney disease, underscoring the need for effective interventions to attenuate inflammation in the post-stenotic kidney. Our preliminary data suggest that treatment with mitochondria-targeted peptides decreases tissue damage and improves renal function in the swine stenotic-kidney, but whether mitoprotection rescues kidney function in a pre-clinical large animal model of MetS+RAS remains unknown. The hypothesis underlying this proposal is that superimposed MetS induces mitochondrial injury and exacerbates it in the stenotic RAS kidney. Hence, mitoprotection would attenuate renal structural and functional impairment that MetS magnifies in the stenotic-kidney, such as apoptosis, fibrosis, oxidative stress, and vascular loss. To test this hypothesis we will take advantage of a novel swine model of MetS with and without RAS that we recently developed that specifically mimics the disease. We will also take advantage of unique physiological imaging techniques to study single-kidney function and structure in-vivo and ex-vivo.
Three specific aims will be pursued:
Specific Aim 1 will test the hypothesis that MetS induces progressive renal mitochondrial damage and dysfunction.
Specific Aim 2 will test the hypothesis that MetS exacerbates renal mitochondrial dysfunction in RAS.
Specific Aim 3 will test the hypothesis that mitoprotection preserves renal structure and function in MetS+RAS. The proposed studies could allow rational development of adequate treatment strategies to ameliorate renal dysfunction in patients with MetS+RAS. This proposal is well aligned with the applicant's career goals and will provide him with unique skills from theoretical and experimental knowledge to technical proficiency required for his future independent career.

Public Health Relevance

There is a pressing need for effective interventions to preserve the post-stenotic kidney in subjects with metabolic syndrome and renal artery stenosis. This study could allow rational development of adequate mitoprotective strategies to ameliorate renal dysfunction in these patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK106427-04
Application #
9531351
Study Section
Kidney, Urologic and Hematologic Diseases D Subcommittee (DDK)
Program Officer
Rankin, Tracy L
Project Start
2015-08-01
Project End
2020-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Eirin, Alfonso; Textor, Stephen C; Lerman, Lilach O (2018) Emerging Paradigms in Chronic Kidney Ischemia. Hypertension 72:1023-1030
Meng, Yu; Eirin, Alfonso; Zhu, Xiang-Yang et al. (2018) The metabolic syndrome modifies the mRNA expression profile of extracellular vesicles derived from porcine mesenchymal stem cells. Diabetol Metab Syndr 10:58
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
Yuan, Fang; Woollard, John R; Jordan, Kyra L et al. (2018) Mitochondrial targeted peptides preserve mitochondrial organization and decrease reversible myocardial changes in early swine metabolic syndrome. Cardiovasc Res 114:431-442
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
Yuan, Fang; Hedayat, Ahmad F; Ferguson, Christopher M et al. (2018) Mitoprotection attenuates myocardial vascular impairment in porcine metabolic syndrome. Am J Physiol Heart Circ Physiol 314:H669-H680
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
Eirin, Alfonso; Hedayat, Ahmad F; Ferguson, Christopher M et al. (2018) Mitoprotection preserves the renal vasculature in porcine metabolic syndrome. Exp Physiol 103:1020-1029
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
Sun, In O; Santelli, Adrian; Abumoawad, Abdelrhman et al. (2018) Loss of Renal Peritubular Capillaries in Hypertensive Patients Is Detectable by Urinary Endothelial Microparticle Levels. Hypertension 72:1180-1188

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