新型STING抑制剂H151对肾缺血再灌注急性肾损伤的保护作用

IF 3.7 2区 医学 Q1 PHYSIOLOGY American Journal of Physiology-renal Physiology Pub Date : 2023-06-01 Epub Date: 2023-04-27 DOI:10.1152/ajprenal.00004.2023
Zhijian Hu, Fangming Zhang, Max Brenner, Asha Jacob, Ping Wang
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引用次数: 0

摘要

肾缺血再灌注(RIR)引起的急性肾损伤(AKI)是一种常见的肾功能障碍,发病率和死亡率都很高。干扰素(IFN)基因刺激因子(STING)是介导炎症和损伤的胞质dna激活信号通路。我们最近的研究表明,细胞外冷诱导rna结合蛋白(eCIRP)是一种新发现的损伤相关分子模式,可激活STING并加剧失血性休克。H151是一种选择性结合STING并抑制STING介导活性的小分子。我们假设H151在体外减弱了ecirp诱导的STING激活,在体内抑制了rir诱导的AKI。在体外,用eCIRP培养的肾小管上皮细胞显示IFN-β、STING通路下游细胞因子、IL-6、肿瘤坏死因子-α和中性粒细胞明胶酶相关脂钙素水平升高,而与eCIRP和H151共培养以剂量依赖的方式降低了这些升高。在体内,双侧肾缺血再灌注后24 h, rir -载体处理小鼠肾小球滤过率降低,而rir - h151处理小鼠肾小球滤过率不变。与假手术相比,血清尿素氮、肌酐和中性粒细胞明胶酶相关的脂钙蛋白在rir -载体中升高,但在RIR-H151中,这些水平明显低于rir -载体。与假手术组相比,小鼠肾脏IFN-β mRNA、组织学损伤评分和TUNEL染色均升高,而小鼠肾脏IFN-β mRNA、组织学损伤评分和TUNEL染色均明显降低。重要的是,与假手术相比,在10天的生存研究中,rir -载体的生存率降至25%,但RIR-H151的生存率为63%。结论:H151抑制ecirp诱导的肾小管上皮细胞STING活化。因此,H151抑制STING可能是一种有希望的治疗rir诱导AKI的干预措施。肾缺血再灌注(RIR)引起的急性肾损伤(AKI)是一种常见的肾功能障碍,发病率和死亡率都很高。干扰素基因刺激因子(STING)是胞质dna激活的信号通路,负责介导炎症和损伤。细胞外冷诱导rna结合蛋白(eCIRP)激活STING并加剧失血性休克。H151是一种新型的STING抑制剂,能减弱体外ecirp诱导的STING激活,抑制rir诱导的AKI。H151有望作为rir诱导的AKI的治疗干预手段。
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The protective effect of H151, a novel STING inhibitor, in renal ischemia-reperfusion-induced acute kidney injury.

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.

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来源期刊
CiteScore
8.40
自引率
7.10%
发文量
154
审稿时长
2-4 weeks
期刊介绍: The American Journal of Physiology - Renal Physiology publishes original manuscripts on timely topics in both basic science and clinical research. Published articles address a broad range of subjects relating to the kidney and urinary tract, and may involve human or animal models, individual cell types, and isolated membrane systems. Also covered are the pathophysiological basis of renal disease processes, regulation of body fluids, and clinical research that provides mechanistic insights. Studies of renal function may be conducted using a wide range of approaches, such as biochemistry, immunology, genetics, mathematical modeling, molecular biology, as well as physiological and clinical methodologies.
期刊最新文献
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