急性肾损伤(AKI)表现为以代谢废物快速积累为特征的临床综合征。如血肌酐和尿素氮,导致肾功能突然下降.目前,缺乏针对AKI的特异性治疗药物。以前,我们确定胃泌素释放肽受体(GRPR)是AKI的致病因子。在这项研究中,我们研究了一种新型中药单体的治疗潜力,auantiamide(AA),与我们之前报道的GRPR拮抗剂结构相似,RH-1402.我们使用各种AKI模型在体外和体内比较了AA与RH-1402的治疗功效。我们的研究结果表明,在体外,AA减毒损伤,坏死,反复缺氧/复氧和脂多糖刺激的人肾小管上皮细胞的炎症反应。在体内,AA改善缺血/再灌注和盲肠结扎穿刺诱导的AKI小鼠模型的肾小管损伤和炎症,超越RH-1402的功效。此外,分子对接和细胞热转移试验证实GRPR是AA的直接靶标,在原代细胞中进一步验证。值得注意的是,在GRPR沉默的HK-2细胞和GRPR系统敲除小鼠中,AA未能减轻肾脏炎症和损伤,强调GRPR在AA作用机制中的重要性。总之,我们的研究表明,AA是GRPR的新型拮抗剂,也是治疗AKI的有前景的临床候选药物.
Acute kidney injury (AKI) manifests as a clinical syndrome characterised by the rapid accumulation of metabolic wastes, such as blood creatinine and urea nitrogen, leading to a sudden decline in renal function. Currently, there is a lack of specific therapeutic drugs for AKI. Previously, we identified gastrin-releasing peptide receptor (GRPR) as a pathogenic factor in AKI. In this study, we investigated the therapeutic potential of a novel Chinese medicine monomer, aurantiamide (AA), which exhibits structural similarities to our previously reported GRPR antagonist, RH-1402. We compared the therapeutic efficacy of AA with RH-1402 both in vitro and in vivo using various AKI models. Our results demonstrated that, in vitro, AA attenuated injury, necroptosis, and inflammatory responses in human renal tubular epithelial cells subjected to repeated hypoxia/reoxygenation and lipopolysaccharide stimulation. In vivo, AA ameliorated renal tubular injury and inflammation in mouse models of ischemia/reperfusion and cecum ligation puncture-induced AKI, surpassing the efficacy of RH-1402. Furthermore, molecular docking and cellular thermal shift assay confirmed GRPR as a direct target of AA, which was further validated in primary cells. Notably, in GRPR-silenced HK-2 cells and GRPR systemic knockout mice, AA failed to mitigate renal inflammation and injury, underscoring the importance of GRPR in AA\'s mechanism of action. In conclusion, our study has demonstrated that AA serve as a novel antagonist of GRPR and a promising clinical candidate for AKI treatment.