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 (IFN) 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 hypothesized that H151 attenuates eCIRP-induced STING activation in vitro and inhibits RIR-induced AKI in vivo. In vitro, renal tubular epithelial cells incubated with eCIRP showed increased levels of IFN-β, STING pathway downstream cytokine, IL-6, tumor necrosis factor-α, and neutrophil gelatinase-associated lipocalin, whereas coincubation with eCIRP and H151 diminished those increases in a dose-dependent manner. In vivo, 24 h after bilateral renal ischemia-reperfusion, glomerular filtration rate was decreased in RIR-vehicle-treated mice, whereas glomerular filtration rate was unchanged in RIR-H151-treated mice. In contrast to sham, serum blood urea nitrogen, creatinine, and neutrophil gelatinase-associated lipocalin 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 renal tubular epithelial cells. Therefore, STING inhibition by H151 can be a promising therapeutic intervention for RIR-induced AKI.NEW & NOTEWORTHY Renal ischemia-reperfusion (RIR)-induced acute kidney injury (AKI) is a common renal functional disorder with a high morbidity and mortality rate. Stimulator of interferon genes (STING) is the cytosolic DNA-activated signaling pathway responsible for mediating inflammation and injury. Extracellular cold-inducible RNA-binding protein (eCIRP) activates STING and exacerbates hemorrhagic shock. H151, a novel STING inhibitor, attenuated eCIRP-induced STING activation in vitro and inhibited RIR-induced AKI. H151 shows promise as a therapeutic intervention for RIR-induced AKI.

• Authors: Zhijian Hu, Fangming Zhang, Max Brenner, Asha Jacob, Ping Wang
• Journal: American journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 324 Issue 6 Pg. F558-F567 (06 01 2023) ISSN: 1522-1466 [Electronic] United States
• PMID: 37102684 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Lipocalin-2
• Interferons
• RNA-Binding Proteins

Topics

• Mice
• Animals
• Lipocalin-2 (metabolism)
• Shock, Hemorrhagic (complications, metabolism, pathology)
• Reperfusion Injury (complications, prevention & control, metabolism)
• Acute Kidney Injury (metabolism)
• Ischemia (metabolism)
• Kidney (metabolism)
• Reperfusion
• Interferons (metabolism, pharmacology, therapeutic use)
• Inflammation (metabolism)
• RNA-Binding Proteins (metabolism, pharmacology, therapeutic use)