The novel STING antagonist H151 ameliorates cisplatin-induced acute kidney injury and mitochondrial dysfunction

Abstract

Stimulator of interferon genes (STING) is an important adaptor in the cytosolic DNA sensing pathways. Recent study found that the deletion of STING ameliorated cisplatin-induced acute kidney injury (AKI), suggesting that STING could serve as a potential target for AKI therapy. Up to now, a series of small-molecule STING inhibitors/antagonists have been identified. However, none of research was performed to explore the role of human STING inhibitors in AKI. Here we investigated the effect of a newly generated covalent antagonist H151 targeting both human and murine STING, in cisplatin-induced AKI. We found that H151 treatment significantly ameliorated cisplatin-induced kidney injury as shown by the improvement of renal function, kidney morphology and renal inflammation. Besides, tubular cell apoptosis and the increased renal tubular injury marker NGAL induced by cisplatin were also effectively attenuated in H151-treated mice. Moreover, the mitochondrial injury caused by cisplatin was also reversed as evidenced by the improved mitochondrial morphology, restored mitochondrial DNA (mtDNA) content, and reversed mitochondrial genes expression. Finally, we observed enhanced mtDNA levels in the plasma of patients receiving platinum-based chemotherapy compared to the healthy controls, which could potentially activate STING signaling. Taken together, these findings suggested that H151 could be a potential therapeutic agent for treating AKI possibly through inhibiting STING-mediated inflammation and mitochondrial injury.