Stratifin(SFN)is a member of the 14-3-3 family of highly conserved soluble acidic proteins,which regulates a variety of cellular activities such as cell cycle,cell growth and development,cell survival and death,and gene transcription.Acute kidney injury(AKI)is prevalent disorder characterized by inflammatory response,oxidative stress,and programmed cell death in renal tubular epithelial cells,but there is still a lack of effective therapeutic target for AKI.In this study,we investigated the role of SFN in AKI and the underlying mechanisms.We established ischemic and nephrotoxic AKI mouse models caused by ischemia-reperfusion(I/R)and cisplatin,respectively.We conducted proteomic and immunohistochemical analyses and found that SFN expression levels were significantly increased in AKI patients,cisplatin-or I/R-induced AKI mice.In cisplatin-or hypoxia/reoxygenation(H/R)-treated human proximal tubule epithelial cells(HK2),we showed that knockdown of SFN significantly reduced the expression of kidney injury marker Kim-1,attenuated programmed cell death and inflammatory response.Knockdown of SFN also significantly alleviated the decline of renal function and histological damage in cisplatin-caused AKI mice in vivo.We further revealed that SFN bound to RIPK3,a key signaling modulator in necroptosis,to induce necroptosis and the subsequent inflammation in cisplatin-or H/R-treated HK2 cells.Overexpression of SFN increased Kim-1 protein levels in cisplatin-treated MTEC cells,which was suppressed by RIPK3 knockout.Taken together,our results demonstrate that SFN that enhances cisplatin-or I/R-caused programmed cell death and inflammation via interacting with RIPK3 may serve as a promising therapeutic target for AKI treatment.

Fang Wang;Jia-nan Wang;Xiao-yan He;Xiao-guo Suo;Chao Li;Wei-jian Ni;Yu-ting Cai;Yuan He;Xin-yun Fang;Yu-hang Dong;Tian Xing;Ya-ru Yang;Feng Zhang;Xiang Zhong;Hong-mei Zang;Ming-ming Liu;Jun Li;Xiao-ming Meng;Juan Jin

Inflammation and Immune Mediated Diseases Laboratory of Anhui Province,Anhui Institute of Innovative Drugs,School of Pharmacy,Anhui Medical University,The Key Laboratory of Anti-inflammatory of Immune Medicines,Ministry of Education,Hefei 230032,China;Department of Pharmacy,Anhui Provincial Hospital,The First Affiliated Hospital of USTC,Division of Life Sciences and Medicine,University of Science and Technology of China,Hefei 230001,China;Hospital of Stomatology,Anhui Medical University,Key Laboratory of Oral Diseases Research of Anhui Province,Hefei 230032,China;Department of Pharmacy,Changzheng Hospital,Naval Medical University,Shanghai 200003,China;Department of Nephrology,Sichuan Academy of Medical Sciences&Sichuan Provincial People's Hospital,School of Medicine,University of Electronic Science and Technology of China,Chengdu 610072,China;School of Basic Medical Sciences,Anhui Medical University,Hefei 230032,China

中国药理学报（英文版）

[1]Fang Wang;Jia-nan Wang;Xiao-yan He;Xiao-guo Suo;Chao Li;Wei-jian Ni;Yu-ting Cai;Yuan He;Xin-yun Fang;Yu-hang Dong;Tian Xing;Ya-ru Yang;Feng Zhang;Xiang Zhong;Hong-mei Zang;Ming-ming Liu;Jun Li;Xiao-ming Meng;Juan Jin-.Stratifin promotes renal dysfunction in ischemic and nephrotoxic AKI mouse models via enhancing RIPK3-mediated necroptosis)[J].中国药理学报（英文版）,2022(02):330-341

Stratifin,nephrotoxic,MTEC

promotes,renal,dysfunction,ischemic,AKI,mouse,models,enhancing,RIPK3,mediated,necroptosis,SFN,member,family,highly,conserved,soluble,acidic,proteins,which,regulates,variety,cellular,activities,such,cycle,growth,development,survival,death,gene,transcription,Acute,kidney,injury,prevalent,disorder,characterized,by,inflammatory,response,oxidative,stress,programmed,tubular,epithelial,cells,but,there,still,lack,effective,therapeutic,target,In,this,study,investigated,role,underlying,mechanisms,We,established,caused,ischemia,reperfusion,cisplatin,respectively,conducted,proteomic,immunohistochemical,analyses,found,that,levels,were,significantly,increased,patients,induced,mice,hypoxia,reoxygenation,treated,human,proximal,tubule,HK2,showed,knockdown,reduced,marker,Kim,attenuated,Knockdown,also,alleviated,decline,histological,damage,vivo,further,revealed,bound,key,signaling,modulator,subsequent,inflammation,Overexpression,was,suppressed,knockout,Taken,together,our,results,demonstrate,enhances,interacting,may,promising,treatment

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