Chromodomain Y‐like(CDYL)inhibition ameliorates acute kidney injury in mice by regulating tubular pyroptosis  

作　　者：Ting Xiang Ling-zhi Li Jin-xi Li Xin-yun Chen Fan Guo Jing Liu Yi-ting Wu Lin Lin Rui-han Xu Hui-ping Wang Liang Ma Ping Fu 

机构地区：[1]Department of Nephrology,Institute of Kidney Diseases,West China Hospital of Sichuan University,and National Key Laboratory of Kidney Diseases,Chengdu 610041,China [2]West-District Outpatient Department,West China Hospital of Stomatology,Sichuan University,Chengdu 610041,China [3]West China School of Medicine,Sichuan University,Chengdu 610041,China

出　　处：《Acta Pharmacologica Sinica》2024年第12期2598-2610,共13页中国药理学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(82370737 to LM and 82100775 to LL);the 1.3.5 project for disciplines of excellence from West China Hospital of Sichuan University(ZYGD23015 to PF).

摘　　要：Acute kidney injury(AKI)is a common disease,but lacking effective drug treatments.Chromodomain Y‐like(CDYL)is a kind of chromodomain protein that has been implicated in transcription regulation of autosomal dominant polycystic kidney disease.Benzo[d]oxazol-2(3H)-one derivative(compound D03)is the first potent and selective small-molecule inhibitor of CDYL(KD=0.5μM).In this study,we investigated the expression of CDYL in three different models of cisplatin(Cis)-,lipopolysaccharide(LPS)-and ischemia/reperfusion injury(IRI)-induced AKI mice.By conducting RNA sequencing and difference analysis of kidney samples,we found that tubular CDYL was abnormally and highly expressed in injured kidneys of AKI patients and mice.Overexpression of CDYL in cisplatin-induced AKI mice aggravated tubular injury and pyroptosis via regulating fatty acid binding protein 4(FABP4)-mediated reactive oxygen species production.Treatment of cisplatin-induced AKI mice with compound D03(2.5 mg·kg^(-1)·d^(-1),i.p.)effectively attenuated the kidney dysfunction,pathological damages and tubular pyroptosis without side effects on liver or kidney function and other tissue injuries.Collectively,this study has,for the first time,explored a novel aspect of CDYL for tubular epithelial cell pyroptosis in kidney injury,and confirmed that inhibition of CDYL might be a promising therapeutic strategy against AKI.

关 键 词：acute kidney injury tubular epithelial cell chromodomain Y‐like PYROPTOSIS fatty acid-binding protein 4 benzo[d]oxazol-2(3H)-one 

分 类 号：R692[医药卫生—泌尿科学]