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).
AKI accounts for ~$10 billion in US healthcare costs and results in 2 million deaths annually worldwide. There are no effective clinical therapies that reduce the severity of injury or accelerate recovery after AKI. In this proposal, we will confirm HDAC8 as a therapeutic target for promoting productive repair after AKI, and develop novel HDAC8 inhibitors with improved potency, drug-like properties, and efficacy, that have the potential to advance into clinical trails to treat AKI.
