# Mitochondrial injury interferes with endogenous renal repair in experimental renovascular disease

> **NIH NIH R03** · MAYO CLINIC ROCHESTER · 2020 · $119,250

## Abstract

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 th...

## Key facts

- **NIH application ID:** 9955256
- **Project number:** 5R03DK122137-02
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Alfonso Eirin
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $119,250
- **Award type:** 5
- **Project period:** 2019-07-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9955256

## Citation

> US National Institutes of Health, RePORTER application 9955256, Mitochondrial injury interferes with endogenous renal repair in experimental renovascular disease (5R03DK122137-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9955256. Licensed CC0.

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