This application responds to PAR-18-103, ?Small Grant Program for NIDDK K01/K08/K23 Recipients (R03)?, which provides NIDDK-supported K01, K08, and K23 recipients support at some point during the final two years of their K award, as they complete their transition to fully independent investigator status. Renovascular disease (RVD) remains an important cause of renal failure in the aging population. My K08 studies showed that RVD in swine induces mitochondrial injury in tubular cells, but whether this reflects the direct effect of ischemia and metabolic abnormalities on tubular cells or defective endogenous repair in the post-stenotic kidney is unknown. RVD presents repeated episodes of insults mimicking acute kidney injury (AKI) from which the kidney can normally recover. CD133+/CD24+ scattered tubular-like cells (STCs) represent a dedifferentiated phenotype that can be adopted by surviving tubular epithelial cells. STCs can proliferate and re-differentiate to replace lost neighboring cells. Our preliminary data suggest that RVD induces structural and functional abnormalities in the swine STC mitochondria, but whether RVD impairs the recovery potential of the kidney is unknown. Detecting STC dysfunction and elucidating the mechanisms responsible may facilitate development of adequate tools to preserve their reparative potency and kidney vitality. The hypothesis underlying this proposal is that RVD induces STC mitochondrial injury that impairs their integrity and function, blunting their overall capacity to repair the kidney. We will employ novel swine models of renal artery stenosis (RAS), metabolic syndrome (MetS), and MetS+RAS that closely mimic the ischemic and metabolic components of human RVD. We will study the efficacy of STCs in a murine model of ischemia reperfusion injury (IRI)-induced AKI. Delivery of swine STCs pretreated with mitochondria-targeted peptides (MTPs) will establish the contribution of mitochondrial dysfunction to STC impairment in RVD.
Two specific aims will be pursued:
Specific Aim 1 will test the hypothesis that RVD-induced STC mitochondrial injury affects their integrity and function. STCs will be collected from pigs after 16 weeks of Lean or MetS diet with or without RAS. Mitochondrial structure and function, as well as cellular injury and function will be assessed in primary cultures of STCs with and without pre-incubation with MTPs.
Specific Aim 2 will test the hypothesis that RVD-induced mitochondrial injury in STCs blunts their capacity to repair in-vivo kidneys after AKI. AKI (IRI) will be induced in mice, and STCs (from Specific Aim 1) or vehicle will be intra-arterially injected 3 days after AKI. Renal function and fibrosis will be studied 2 weeks later. The proposed studies could greatly advance our understanding the vulnerability of this repair system and contribute towards development of strategies for improving the utility and efficacy of kidney repair in renal disease. 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 for his future independent career.

Public Health Relevance

/Public health relevance There is a pressing need for effective interventions to preserve the post-stenotic kidney in subjects with renovascular disease, a common cause of secondary hypertension and renal failure in the aging population. This proposal tests the hypothesis that renovascular disease blunts the overall renal repair capacity, which could be prevented and/or restored by protecting mitochondria, organelles that modulate several important cellular functions. These studies could allow rational development of adequate strategies for improving the utility and efficacy of kidney repair in patients with renovascular disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Small Research Grants (R03)
Project #
5R03DK122137-02
Application #
9955256
Study Section
Kidney, Urologic and Hematologic Diseases D Subcommittee (DDK)
Program Officer
Rankin, Tracy L
Project Start
2019-07-01
Project End
2021-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905