# Therapeutic Optimization of Productive Repair After Acute Kidney Injury

> **NIH NIH UC2** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $630,202

## Abstract

Acute kidney injury (AKI) is a heterogeneous condition caused by a range of injurious stimuli that
affects >1.5 million patients in the US each year. Ultimately, AKI accounts for ~$10 billion in US
healthcare costs and results in 2 million deaths annually worldwide. AKI has long-term health
consequences ranging from new onset of hypertension with mild chronic kidney disease (CKD),
to progressive CKD ultimately leading to kidney failure. Despite this, there are no effective clinical
therapies that reduce the severity of injury or accelerate recovery after AKI. To solve this, we have
assembled a multidisciplinary team with expertise in zebrafish, mouse, and human kidney
organoid models of AKI. Our team previously discovered a novel compound 4-
phenylthiobutanoate (PTBA) that when delivered as a prodrug (UPHD25 or UPHD186)
ameliorates injury in models after AKI. PTBA inhibits histone deacetylase-8 (HDAC8), which plays
a major role in deacetylating the cohesin subunit SMC3 (involved in sister chromatid cohesion
and the formation of gene-regulatory chromatin loops). In vitro studies have shown that HDAC8
inhibition leads to sustained SMC3 acetylation and delays cell cycle progression, without
compromising mitosis. In vivo mouse data shows that PTBA increases the proportion of cells in
G0/G1 and reduces the number of cells in G2/M after AKI. As tubular epithelial cells (TECs) can
arrest in a pro-fibrotic state in G2/M due to AKI-induced DNA damage, we hypothesize that PTBA’s
inhibition of HDAC8 promotes recovery from AKI by slowing down the cell cycle, giving TECs
more time to repair DNA damage and thus reducing the likelihood of arresting in G2/M. We will
test this hypothesis in two projects that will (1) Confirm HDAC8 as a therapeutic target for
promoting productive repair after AKI, (2) Develop novel HDAC8 inhibitors with improved potency,
drug-like properties, and efficacy that can ultimately be taken into clinical trials. Our highly
collaborative and complementary team is well placed to conduct this work with expertise in
medicinal chemistry and compound optimization (Hukriede, Huryn); and models of AKI in
mammals (de Caestecker); zebrafish (Hukriede, Davidson); cell culture and human kidney
organoids (Davidson, Hukriede).

## Key facts

- **NIH application ID:** 10058728
- **Project number:** 1UC2DK126122-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Alan Davidson
- **Activity code:** UC2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $630,202
- **Award type:** 1
- **Project period:** 2020-09-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10058728

## Citation

> US National Institutes of Health, RePORTER application 10058728, Therapeutic Optimization of Productive Repair After Acute Kidney Injury (1UC2DK126122-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10058728. Licensed CC0.

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