# Novel Regulation of Renal Function by S-Nitrosylation

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2024 · $540,667

## Abstract

PROJECT SUMMARY/ABSTRACT
Acute kidney injury (AKI) is a severe clinical syndrome that develops in up to 15% of all
hospitalized patients and up to 50% intensive care unit patients. Severe AKI results in tubulointerstitial
fibrosis and progressive loss of kidney function, which are associated with increased long-term
morbidity and mortality. Productive kidney repair (also called kidney adaptive repair) can restore
nephron function and avoid tubulointerstitial fibrosis; therefore, promoting productive repair is an
attractive target in therapeutic treatment of AKI. Nitric oxide (NO) is an established mediator in repair
of skin, nerve, skeletal muscle, liver, heart, bone, and vessels, but its role in kidney repair remains
entirely unknown. NO-based signaling is conveyed in large part by protein S-nitrosylation. We have
discovered a novel protein S-nitrosylation system in kidney consisting of the novel nitrosylase SCAN
and its cognate denitrosylase SCoR, which add and remove SNO groups on target proteins,
respectively. Pyruvate Kinase M2 (PKM2) is a critical regulator of cell metabolism, and is a major S-
nitrosylation target of the SCAN/SCoR system during kidney injury. We now find that SCAN/SCoR and
PKM2 are also important during kidney repair. Deletion of SCoR in mice, which increases SCAN
mediated S-nitrosylation, promotes adaptive repair through multiple beneficial effects: 1) alleviating
oxidative stress; 2) increasing availability of biosynthetic macromolecules; 3) increasing cell cycle re-
entry; 4) reversal of G2/M arrest; 5) reducing AKI-associated kidney fibrosis. Reduced SCoR activity
and increased SCAN expression are observed in human AKI kidney compared with healthy kidney,
suggesting that S-nitrosylation regulated by the SCAN/SCoR system is important in human kidney
repair. We have developed a specific SCoR inhibitor as a tool to assess the therapeutic potential of
SCoR inhibition in productive kidney repair. To explore the role of PKM2 S-nitrosylation regulated by
the SCAN/SCoR system in kidney repair, and to assess the efficacy of SCoR inhibition in repair, we
will: 1) define the role of SCoR in productive kidney repair; 2) delineate the role of SCAN and S-
nitrosylation of PKM2 in kidney repair; 3) determine the clinical significance of SCoR and SCAN in
kidney repair. Successful completion of our studies not only will reveal the physiological function of
PKM2 S-nitrosylation catalyzed by SCAN and SCoR enzymes in productive repair, but also will define
and validate new drug targets to repair the kidneys after AKI.

## Key facts

- **NIH application ID:** 10801357
- **Project number:** 2R01DK119506-06
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** JONATHAN S. STAMLER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $540,667
- **Award type:** 2
- **Project period:** 2018-09-25 → 2027-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10801357

## Citation

> US National Institutes of Health, RePORTER application 10801357, Novel Regulation of Renal Function by S-Nitrosylation (2R01DK119506-06). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/10801357. Licensed CC0.

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