典型文献
Selective EZH2 inhibitor zldl039 alleviates inflammation in cisplatin-induced acute kidney injury partially by enhancing RKIP and suppressing NF-κB p65 pathway
文献摘要：
Enhancer of zeste homolog 2(EZH2),a component of polycomb repressive complex 2(PRC2),is a histone lysine methyltransferase mediating trimethylation of histone H3 at lysine 27(H3K27me3),which is a repressive marker at the transcriptional level.EZH2 sustains normal renal function and its overexpression has bad properties.Inhibition of EZH2 overexpression exerts protective effect against acute kidney injury(AKI).A small-molecule compound zld1039 has been developed as an efficient and selective EZH2 inhibitor.In this study,we evaluated the efficacy of zld1039 in the treatment of cisplatin-induced AKI in mice.Before injection of cisplatin(20mg/kg,i.p.),mice were administered zld1039(100,200mg/kg,i.g.)once,then in the following 3 days.We found that cisplatin-treated mice displayed serious AKI symptoms,evidenced by kidney dysfunction and kidney histological injury,accompanied by EZH2 upregulation in the nucleus of renal tubular epithelial cells.Administration of zld1039 dose-dependently alleviated renal dysfunction as well as the histological injury,inflammation and cell apoptosis in cisplatin-treated mice.We revealed that zld1039 administration exerted an anti-inflammatory effect in kidney of cisplatin-treated mice via H3K27me3 inhibition,raf kinase inhibitor protein(RKIP)upregulation and NF-κB p65 repression.In the cisplatin-treated mouse renal tubular epithelial(TCMK-1)cells,silencing of RKIP with siRNA did not abolish the anti-inflammatory effect of EZH2 inhibition,suggesting that RKIP was partially involved in the anti-inflammatory effect of zld1039.Collectively,EZH2 inhibition alleviates inflammation in cisplatin-induced mouse AKI via upregulating RKIP and blocking NF-κB p65 signaling in cisplatin-induced AKI.The potent and selective EZH2 inhibitor zld1039 has the potential as a promising agent for the treatment of AKI.
文献关键词：
中图分类号：
作者姓名：
Li Wen;Shao-hua Tao;Fan Guo;Ling-zhi Li;Hong-liu Yang;Yan Liang;Li-dan Zhang;Liang Ma;Ping Fu
作者机构：
Kidney Research Institute,National Clinical Research Center for Geriatrics and Division of Nephrology,West China Hospital of Sichuan University,Chengdu 610041,China;Research Core Facility of West China Hospital,Chengdu 610041,China;Laboratory of Anesthesia&Critical Care Medicine,Translational Neuroscience Center,West China Hospital of Sichuan University,Chengdu 610041,China
文献出处：
引用格式：
[1]Li Wen;Shao-hua Tao;Fan Guo;Ling-zhi Li;Hong-liu Yang;Yan Liang;Li-dan Zhang;Liang Ma;Ping Fu-.Selective EZH2 inhibitor zldl039 alleviates inflammation in cisplatin-induced acute kidney injury partially by enhancing RKIP and suppressing NF-κB p65 pathway)[J].中国药理学报（英文版）,2022(08):2067-2080
A类：
zldl039,zld1039,TCMK
B类：
Selective,EZH2,inhibitor,alleviates,inflammation,cisplatin,induced,acute,kidney,injury,partially,by,enhancing,RKIP,suppressing,p65,pathway,Enhancer,zeste,homolog,component,polycomb,repressive,complex,PRC2,histone,lysine,methyltransferase,mediating,trimethylation,H3K27me3,which,marker,transcriptional,level,sustains,normal,renal,its,overexpression,has,bad,properties,Inhibition,exerts,protective,effect,against,AKI,small,molecule,compound,been,developed,efficient,selective,this,study,evaluated,efficacy,treatment,mice,Before,injection,20mg,were,administered,200mg,once,then,following,days,We,found,that,treated,displayed,serious,symptoms,evidenced,dysfunction,histological,accompanied,upregulation,nucleus,tubular,epithelial,cells,Administration,dose,dependently,alleviated,well,apoptosis,revealed,administration,exerted,anti,inflammatory,inhibition,raf,kinase,protein,repression,mouse,silencing,siRNA,did,not,abolish,suggesting,was,involved,Collectively,upregulating,blocking,signaling,potential,promising,agent
AB值：
0.470694
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