HDAC3 inhibitor RGFP966 mitigates acute kidney injury by modulating RIPK1-mediated programmed necrosis

Abstract Acute kidney injury (AKI) refers to clinical syndromes culminating in sharp reduction in renal function over a short period of time because of various reasons. These syndromes manifest in the form of inflammation and apoptosis of renal tubular epithelial cells via controlled demise. Histone deacetylases are critical in renal physiology and fibrosis. Here, the HDAC3 expression was shown to be upregulated and localized predominantly in the renal tubules in an AKI mouse model. Moreover, the selective HDAC3 inhibitor RGFP966 was found to reduce inflammation and injury caused by cisplatin and hypoxia–reoxygenation in HK2 cells. Importantly, RGFP966 exerted potent protective effects in mouse models of ischemia/reperfusion-induced AKI and cisplatin. Furthermore, RNA sequencing revealed that RGFP966 significantly inhibited the upregulation of RIPK1. Cellular thermal displacement assay and molecular docking demonstrated the physical binding of RGFP966 to HDCA3. In addition, RIPK1 knockdown cell assay signified that RGFP966 directly targeted RIPK1 and inhibited RIPK1 kinase activity. In summary, these findings established the efficacy of the HDAC3 inhibitor RGFP966 in treating AKI.