USP11 promotes renal tubular cell pyroptosis and fibrosis in UUO mice via inhibiting KLF4 ubiquitin degradation  

作　　者：Xin Wang Xin Xie Jia-yun Ni Jing-yao Li Xi-ang Sun Hong-yan Xie Ning-hao Yang Heng-jiang Guo Li Lu Ming Ning Li Zhou Jun Liu Chen Xu Wei Zhang Yi Wen Qian Shen Hong Xu Li-min Lu 

机构地区：[1]Department of Physiology and Pathophysiology,School of Basic Medical Sciences,Fudan University,Shanghai 200032,China [2]Department of Nephrology,Children's Hospital of Fudan University,Shanghai 201103,China [3]Department of Nephrology,Zhongda Hospital,Southeast University School of Medicine,Nanjing 210044,China [4]Shanghai Kidney Development and Pediatric Kidney Disease Research Center,Children's Hospital of Fudan University,Shanghai 201102,China [5]National Clinical Research Center for Aging and Medicine,Huashan Hospital,Fudan University,Shanghai 200040,China

出　　处：《Acta Pharmacologica Sinica》2025年第1期159-170,共12页中国药理学报(英文版)

基　　金：This research was financially supported by the National Natural Science Foundation of China(82370695,82070712);to L Lu and(81900623,82270728);to Y Wen.Shanghai Natural Science Foundation(21ZR1409000);to W Zhang.National Clinical Research Center for Aging and Medicine,Huashan Hospital,Fudan University(2024KF2004);to L Lu.Special Basic Cooperative Research Programs of Yunnan Provincial Undergraduate Universities'Association(202301BA070001-047);to L Lu.We are grateful to Pro.Bicheng Liu(Southeast University,Nanjing)and Hui-juan Wu(Fudan University,Shanghai)for research information and experimental materials.

摘　　要：The pyroptosis of renal tubular epithelial cells leads to tubular loss and inflammation and then promotes renal fibrosis.The transcription factor Kruppel-like factor 4(KLF4)can bidirectionally regulate the transcription of target genes.Our previous study revealed that sustained elevation of KLF4 is responsible for the transition of acute kidney injury(AKl)into chronic kidney disease(CKD)and renal fibrosis.In this study,we explored the upstream mechanisms of renal tubular epithelial cell pyroptosis from the perspective of posttranslational regulation and focused on the transcription factor KLF4.Mice were subjected to unilateral ureteral obstruction(UUO)surgery and euthanized on D7 or D14 for renal tissue harvesting.We showed that the pyroptosis of renal tubular epithelial cells mediated by both the Caspase-1/GSDMD and Caspase-3/GSDME pathways was time-dependently increased in UUO mouse kidneys.Furthermore,we found that the expression of the transcription factor KLF4 was also upregulated in a timedependent manner in UUO mouse kidneys.Tubular epithelial cell-specific Klf4 knockout alleviated UUO-induced pyroptosis and renal fibrosis.In Ang Il-treated mouse renal proximal tubular epithelial cells(MTECs),we demonstrated that KLF4 bound to the promoter regions of Caspase-3 and Caspase-1 and directly increased their transcription.In addition,we found that ubiquitinspecific protease 11(USP11)was increased in UUO mouse kidneys.USP11 deubiquitinated KLF4.Knockout of Usp11 or pretreatment with the USP11 inhibitor mitoxantrone(3 mg/kg,ip.,twice a week for two weeks before UUO surgery)significantly alleviated the increases in KLF4 expression,pyroptosis and renal fibrosis.These results demonstrated that the increased expression of USP11 in renal tubular cells prevents the ubiquitin degradation of KLF4 and that elevated KLF4 promotes inflammation and renal fibrosis by initiating tubular cell pyroptosis.

关 键 词：renal fibrosis renal tubular epithelial cells PYROPTOSIS KLF4 USP11 

分 类 号：R73[医药卫生—肿瘤]