# Dicarboxylic acid therapy for prevention of kidney injury

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $645,599

## Abstract

ABSTRACT
Acute kidney injury (AKI) most commonly occurs in the hospital setting. Hospital-acquired AKI accounts for 22%
of all cases worldwide, and nearly 50% of critically ill inpatients are estimated to suffer from AKI. AKI is associated
with high rates of morbidity and mortality, and causes 2 million deaths per year. The hospitalization cost of AKI
treatment in the US per year is approximately 24 billion. While the kidney may recover, the patients are at a
higher risk for subsequently developing chronic kidney disease (CKD). Other times, the acute injury is so severe
that there is no kidney recovery and ultimately end stage renal disease (ESRD) ensues. Patients that progress
to CKD have hospitalization costs of approximately 100 billion dollars a year in the US. A definitive and effective
treatment for AKI is still lacking, nor are there available interventions to decrease the risk of progression to CKD
after AKI. Current strategies focus on prevention, early diagnosis, and early interventions aimed at managing
the underlying etiologies and complications of AKI. Metabolic signaling during AKI has emerged as an exciting
and potentially druggable target to not only reverse but inhibit proximal tubule damage associated with AKI and
block the subsequent progression to CKD. The majority of metabolic studies in the literature have focused on
protecting the mitochondria, which are known to be damaged during AKI. However, we recently showed that
boosting peroxisomal fatty acid oxidation (FAO) protects against injury in two different mouse models of AKI.
Here, we exploited this protective mechanism by supplementing the diet with peroxisomally-targeted medium-
chain dicarboxylic fatty acids (DCAs). In ischemia/reperfusion injury and nephrotoxic (cisplatin) mouse AKI
models, 7 days of dietary supplementation with an 8-carbon DCA called octanedioc acid (DC8) dramatically
reduced kidney injury and improved function (Similar protection was seen with DC12). We recapitulated the injury
model in vitro, where DCAs conferred protection to human renal proximal tubule epithelial cells (RPTECs). We
propose that DCA is activated to coenzyme-A to form DCA-CoA, which undergoes two rounds of FAO chain-
shortening in peroxisomes to produce DC4-CoA, also known as succinyl-CoA. Peroxisomal succinyl-CoA
maintains high peroxisomal FAO enzyme activity via induction of a post-translational modification (PTM) called
lysine succinylation. Further, peroxisomal FAO enzyme activity hydrolyzes succinyl-CoA to succinate, which is
exported to mitochondria where it drives ATP synthesis through Complex II of the respiratory chain. We
hypothesize that this “quick energy” bolsters the kidney against injury, promoting recovery and limiting
progression to CKD. We expect that DCA metabolically shields the kidney against AKI via peroxisome-
mitochondria metabolic crosstalk this proposal will accelerate the clinical translation of DCA for AKI.

## Key facts

- **NIH application ID:** 10878038
- **Project number:** 1R01DK134346-01A1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** ERIC S GOETZMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $645,599
- **Award type:** 1
- **Project period:** 2024-09-10 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10878038

## Citation

> US National Institutes of Health, RePORTER application 10878038, Dicarboxylic acid therapy for prevention of kidney injury (1R01DK134346-01A1). Retrieved via AI Analytics 2026-06-08 from https://api.ai-analytics.org/grant/nih/10878038. Licensed CC0.

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