HDAC3 inhibition mitigates acute kidney injury by alleviating RIPK1-mediated programmed necrosis
Acute kidney injury (AKI) encompasses a range of clinical syndromes characterized by a rapid decline in renal function, often accompanied by inflammation and the loss of renal tubular epithelial cells. Current research efforts focus on identifying strategies to prevent tubular cell death. Given the involvement of histone deacetylases (HDACs) in renal physiology and their known role in renal fibrosis, we investigated the mechanistic role of HDACs in AKI using a mouse model along with in vitro studies in human renal epithelial cells.
Our findings revealed that HDAC3 expression was significantly upregulated in renal tubules following ischemia/reperfusion injury and cisplatin administration. Notably, treatment with RGFP966, a selective HDAC3 inhibitor, conferred strong protective effects, mitigating AKI in both in vivo and in vitro models. In HK2 cells, RGFP966 reduced inflammation and cellular injury induced by cisplatin and hypoxia-reoxygenation. Transcriptomic analysis further showed that RGFP966 markedly suppressed the induction of RIPK1, a key initiator of necroptosis.
Cellular thermal shift assays and molecular docking confirmed direct binding of RGFP966 to HDAC3. Additionally, RIPK1 knockdown experiments demonstrated that RGFP966 inhibits RIPK1 kinase activity, suggesting that its protective effects are mediated, at least in part, through modulation of necroptotic signaling.
In conclusion, these results establish the therapeutic potential of the HDAC3 inhibitor RGFP966 in the treatment of AKI by targeting HDAC3 and inhibiting RIPK1-mediated necroptosis.