Selective EZH2 inhibitor zldl039 alleviates inflammation in cisplatin-induced acute kidney injury partially by enhancing RKIP and suppressing NF-κB p65 pathway  

作　　者：Li Wen Shao-hua Tao Fan Guo Ling-zhi Li Hong-liu Yang Yan Liang Li-dan Zhang Liang Ma Ping Fu 

机构地区：[1]Kidney Research Institute,National Clinical Research Center for Geriatrics and Division of Nephrology,West China Hospital of Sichuan University,Chengdu,610041,China [2]Research Core Facility of West China Hospital,Chengdu,610041,China [3]Laboratory of Anesthesia&Critical Care Medicine,Translational Neuroscience Center,West China Hospital of Sichuan University,Chengdu,610041,China

出　　处：《Acta Pharmacologica Sinica》2022年第8期2067-2080,共14页中国药理学报（英文版）

基　　金：supported by the National Key R&D Program of China(2020YFC2005000);the National Natural Science Foundation of China(82070711);the Science/Technology Project of Sichuan province(2020YFQ0055);the 1.3.5 project for disciplines of excellence from West China Hospital of Sichuan University(ZYGD18027).

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(20 mg/kg,i.p.),mice were administered zld1039(100,200 mg/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.

关 键 词：acute kidney injury INFLAMMATION enhancer of zeste homolog 2 Raf kinase inhibitor protein NF-κB p65 zld1039 

分 类 号：R285.5[医药卫生—中药学]