Qiao Ruochen, Wang Hui, Li Dasheng, Yang Yu, Shu Jiaxin, Song Xiang, Zhao Xiaozhi, Lu Li
Institute of Translational Medicine the Affiliated Drum Tower Hospital of Nanjing University Medical School Nanjing Jiangsu China.
University College London School of Pharmacy London UK.
Smart Med. 2024 Jun 28;3(2):e20240010. doi: 10.1002/SMMD.20240010. eCollection 2024 Jun.
Recent studies indicate a significant upregulation of gasdermin D (GSDMD) in acute kidney injury (AKI), a severe medical condition characterized by high morbidity and mortality globally. In this study, we identified and validated the therapeutic effects of small molecule inhibitors targeting the GSDMD pathway for AKI treatment. Using a drug screening assay, we evaluated thousands of small molecules from DrugBank against Lipopolysaccharide (LPS) and Nigericin-stimulated immortalized bone marrow-derived macrophages (iBMDMs) to discern GSDMD pathway activators. We simulated AKI in primary renal tubular epithelial cells using hydrogen peroxide (HO) exposure. Furthermore, AKI in mouse models was induced via cisplatin and ischemia/reperfusion. Our findings highlight stevioside as a potent GSDMD activator exhibiting minimal toxicity. Experimental results, both in vitro and in vivo, demonstrate stevioside's significant potential in alleviating renal tubular epithelial cell injury and AKI histological damage. After stevioside treatment, a notable decrease in cleaved GSDMD-N terminal levels was observed coupled with diminished inflammatory factor release. This observation was consistent in both cisplatin- and ischemia/reperfusion-induced AKI mouse models. Collectively, our research suggests that stevioside could be a promising candidate for modulating GSDMD signaling in AKI treatment.
近期研究表明，在急性肾损伤（AKI）中，gasdermin D（GSDMD）有显著上调，急性肾损伤是一种全球发病率和死亡率都很高的严重病症。在本研究中，我们鉴定并验证了靶向GSDMD途径的小分子抑制剂对急性肾损伤治疗的效果。我们使用药物筛选试验，针对脂多糖（LPS）和尼日利亚菌素刺激的永生化骨髓来源巨噬细胞（iBMDMs）评估了DrugBank中的数千种小分子，以识别GSDMD途径激活剂。我们用过氧化氢（HO）处理原代肾小管上皮细胞来模拟急性肾损伤。此外，通过顺铂和缺血/再灌注诱导小鼠模型发生急性肾损伤。我们的研究结果表明，甜菊糖苷是一种有效的GSDMD激活剂，毒性极小。体外和体内实验结果均表明，甜菊糖苷在减轻肾小管上皮细胞损伤和急性肾损伤组织学损伤方面具有显著潜力。甜菊糖苷治疗后，观察到裂解的GSDMD-N末端水平显著降低，同时炎症因子释放减少。这一观察结果在顺铂和缺血/再灌注诱导的急性肾损伤小鼠模型中均一致。总的来说，我们的研究表明，甜菊糖苷可能是急性肾损伤治疗中调节GSDMD信号的一个有前景的候选药物。
