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

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

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The pyroptosis of renal tubular epithelial cells leads to tubular loss and inflammation and then promotes renal fibrosis.The transcription factor Krüppel-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(AKI)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 time-dependent manner in UUO mouse kidneys.Tubular epithelial cell-specific Klf4 knockout alleviated UUO-induced pyroptosis and renal fibrosis.In Ang Ⅱ-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 ubiquitin-specific 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,i.p.,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.

renal fibrosisrenal tubular epithelial cellspyroptosisKLF4USP11

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

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Department of Physiology and Pathophysiology,School of Basic Medical Sciences,Fudan University,Shanghai 200032,China

Department of Nephrology,Children's Hospital of Fudan University,Shanghai 201103,China

Department of Nephrology,Zhongda Hospital,Southeast University School of Medicine,Nanjing 210044,China

Shanghai Kidney Development and Pediatric Kidney Disease Research Center,Children's Hospital of Fudan University,Shanghai 201102,China

National Clinical Research Center for Aging and Medicine,Huashan Hospital,Fudan University,Shanghai 200040,China

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2025

10.1038/s41401-024-01363-z

中国药理学报(英文版)
中科院上海药物研究所

中国药理学报(英文版)

影响因子：0.926
ISSN：1671-4083
年,卷(期)：2025.46(1)