坏死性下垂
药理学
氧化应激
顺铂
程序性细胞死亡
裂谷1
炎症
癌症研究
医学
化学
内科学
免疫学
生物化学
细胞凋亡
化疗
作者
Jianan Wang,Mingming Liu,Fang Wang,Biao Wei,Qin Yang,Yuting Cai,Xin Chen,Xue-Qi Liu,Ling Jiang,Chao Li,Xiaowei Hu,Ju-tao Yu,Tran Ma,Juan Jin,Yuangang Wu,Jun Li,Xiao‐Ming Meng
出处
期刊:Clinical Science
[Portland Press]
日期:2019-07-01
卷期号:133 (14): 1609-1627
被引量:62
摘要
Abstract Acute kidney injury (AKI) is a destructive clinical condition induced by multiple insults including ischemic reperfusion, nephrotoxic drugs and sepsis. It is characterized by a sudden decline in renal function, in addition to excessive inflammation, oxidative stress and programmed cell death of renal tubular epithelial cells. RIPK1-mediated necroptosis plays an important role in AKI. In the present study, we evaluated the treatment effects of Compound-71 (Cpd-71), a novel RIPK1 inhibitor, by comparing with Necrostatin-1 (Nec-1), a classic RIPK1 inhibitor, which has several drawbacks like the narrow structure–activity relationship (SAR) profile, moderate potency and non-ideal pharmacokinetic properties, in vivo and in vitro. Our results showed that pretreatment of Cpd-71 attenuated cisplatin-induced renal injury, restored renal function and suppressed renal inflammation, oxidative stress and cell necroptosis. In addition, Cpd-71 inhibited renal damage while reducing the up-regulated serum creatinine (Cr) and blood urea nitrogen (BUN) levels in established AKI mice model. Consistently, we confirmed that Cpd-71 exhibited more effectively suppressive effect on cisplatin-induced renal tubular cell necroptosis than Nec-1, by physically binding to the allosteric type III ligand binding site of RIPK1, thereby reduced RIPK1 kinase activity, RIPK1/RIPK3 complex formation and phosphor-MLKL membrane translocation by molecular docking, Western blot, co-immunoprecipitation and cellular thermal shift assay (CETSA). Taken together, we currently showed that targeting RIPK1 with Cpd-71 may serve as a promising clinical candidate for AKI treatment.
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