The protective effect of H151, a novel STING inhibitor, in renal ischemia-reperfusion induced acute kidney injury.

Abstract

Renal ischemia-reperfusion (RIR)-induced acute kidney injury (AKI) is a common renal functional disorder with high morbidity and mortality. Stimulator of interferon genes (STING) is the cytosolic DNA-activated signaling pathway that mediates inflammation and injury. Our recent study showed that extracellular cold inducible RNA binding protein (eCIRP), a newly identified damage associated molecular pattern, activates STING and exacerbates hemorrhagic shock. H151 is a small molecule that selectively binds to STING and inhibits STING mediated activity. We hypothesize that H151 attenuates eCIRP-induced STING activation in vitro and inhibits RIR-induced AKI in vivo. In in vitro, renal tubular epithelial cells (RTECs) incubated with eCIRP, showed increased levels of IFN-β, STING pathway downstream cytokine, IL-6, TNF-α and NGAL, whereas co-incubation with eCIRP and H151 diminished those increases in a dose-dependent manner. For in vivo, 24 h after bilateral renal ischemia reperfusion, glomerular filtration rate (GFR) was decreased in RIR-vehicle while GFR was unchanged in RIR-H151 mice. In contrast to sham, serum BUN, creatinine and NGAL were increased in RIR-vehicle but in RIR-H151, these levels were significantly decreased from RIR-vehicle. In contrast to sham, kidney IFN-β mRNA, histological injury score and TUNEL staining were also increased in RIR-vehicle but in RIR-H151, these levels were significantly decreased from RIR-vehicle. Importantly, in contrast to sham, in a 10- day survival study, survival decreased to 25% in RIR-vehicle but RIR-H151 had a survival of 63%. In conclusion, H151 inhibits eCIRP-induced STING activation in RTECs. Therefore, STING inhibition by H151 can be a promising therapeutic intervention for RIR-induced AKI.