# Novel Regulation of Renal Function by S-Nitrosylation

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2020 · $433,805

## Abstract

PROJECT SUMMARY/ABSTRACT
Nitric oxide (NO), generated in the kidney by renal tubular NO synthase (eNOS), can exert renoprotective
effects. However, the mechanisms by which NO does so remain poorly understood. Nitric oxide bioactivity
is principally conveyed by S-nitrosylation of proteins, the oxidative modification of protein thiols by NO to
form S-nitrosothiols (SNOs). Protein S-nitrosylation is reversibly regulated by enzymatic mechanisms
including S-nitrosylases and denitrosylases and accumulating evidence implicates dysregulated S-
nitrosylation in disease. Here, we identify a novel enzymatic machinery subserving protein S-nitrosylation in
the kidney, including a novel metabolic intermediate S-nitroso-coenzyme A (SNO-CoA) that conveys NO
bioactivity and its cognate reductase, SNO-CoA reductase (SCoAR), an enzyme of previously unknown
function that is highly expressed in kidney proximal tubules. SCoAR mediates the breakdown of SNO-CoA
thereby lowering steady-state levels of SNO-proteins (in equilibrium with SNO-CoA). Knockout of SCoAR in
mice (SCoAR-/-) is shown to increase S-nitrosylation within the kidney and to protect against
ischemia/reperfusion (I/R) injury, whereas deletion of eNOS (SCoAR-/-/eNOS-/-) abrogates this protection.
Thus classic renoprotection by eNOS is identified with the SNO-CoA/SCoAR system. Using metabolic
profiling and mass spec (MS)-based SNO-protein identification, we have found that renoprotection by the
SNO-CoA/SCoAR system is likely mediated by metabolic reprogramming within the kidney. Mechanistically,
our data suggest that pyruvate kinase (PKM2) is a major locus of regulation by the SNO-CoA/SCoAR
system during acute kidney injury (AKI). Our grant thus explores the idea that S-nitrosylation of PKM2 is
renoprotective through metabolic reprogramming that entails SCoAR-regulated coordination of fuel
utilization and antioxidant/regenerative defenses. To lay the groundwork for new therapies, we have also
screened for SCoAR inhibitors and successfully developed a new class of drug candidate with nanomolar
potency, which will be studied herein. Thus, our discovery not only reveals the first physiological function of
the SNO-CoA/SCoAR system in mammals, but promises to open a new chapter in our understanding of AKI
with immediate therapeutic implications.
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## Key facts

- **NIH application ID:** 9998940
- **Project number:** 5R01DK119506-03
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** JONATHAN S. STAMLER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $433,805
- **Award type:** 5
- **Project period:** 2018-09-25 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9998940

## Citation

> US National Institutes of Health, RePORTER application 9998940, Novel Regulation of Renal Function by S-Nitrosylation (5R01DK119506-03). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9998940. Licensed CC0.

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