OTUD1 promotes hypertensive kidney fibrosis and injury by deubiquitinating CDK9 in renal epithelial cells  

作　　者：Meng-yang Wang Tian-xiang Yu Qin-yan Wang Xue Han Xiang Hu Shi-ju Ye Xiao-hong Long Yi Wang Hong Zhu Wu Luo Guang Liang 

机构地区：[1]Department of Pharmacy and Institute of Inflammation,Zhejiang Provincial People’s Hospital,Affiliated People’s Hospital,Hangzhou Medical College,Hangzhou,310014,China [2]Chemical Biology Research Center,School of Pharmaceutical Sciences,Wenzhou Medical University,Wenzhou,325035,China [3]Department of Pharmacology,College of Pharmacy,Beihua University,Jilin,132013,China [4]Department of Endocrinology,the First Affiliated Hospital of Wenzhou Medical University,Wenzhou,325035,China [5]School of Pharmaceutical Sciences,Hangzhou Medical College,Hangzhou,310014,China

出　　处：《Acta Pharmacologica Sinica》2024年第4期765-776,共12页中国药理学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(82000793 to WL and 82370829 for HZ);the Key Discipline of Zhejiang Province in Public Health and Preventive Medicine(First Class,Category A)at Hangzhou Medical College.

摘　　要：Hypertensive renal disease (HRD) contributes to the progression of kidney dysfunction and ultimately leads to end-stage renal disease. Understanding the mechanisms underlying HRD is critical for the development of therapeutic strategies. Deubiquitinating enzymes (DUBs) have been recently highlighted in renal pathophysiology. In this study, we investigated the role of a DUB, OTU Domain-Containing Protein 1 (OTUD1), in HRD models. HRD was induced in wild-type or Otud1 knockout mice by chronic infusion of angiotensin II (Ang II, 1 μg/kg per min) through a micro-osmotic pump for 4 weeks. We found that OTUD1 expression levels were significantly elevated in the kidney tissues of Ang II-treated mice. Otud1 knockout significantly ameliorated Ang II-induced HRD, whereas OTUD1 overexpression exacerbated Ang II-induced kidney damage and fibrosis. Similar results were observed in TCMK-1 cells but not in SV40 MES-13 cells following Ang II (1 μM) treatment. In Ang II-challenged TCMK-1 cells, we demonstrated that OTUD1 bound to CDK9 and induced CDK9 deubiquitination: OTUD1 catalyzed K63 deubiquitination on CDK9 with its Cys320 playing a critical role, promoting CDK9 phosphorylation and activation to induce inflammatory responses and fibrosis in kidney epithelial cells. Administration of a CDK9 inhibitor NVP-2 significantly ameliorated Ang II-induced HRD in mice. This study demonstrates that OTUD1 mediates HRD by targeting CDK9 in kidney epithelial cells, suggesting OTUD1 is a potential target in treating this disease.

关 键 词：hypertensive renal disease OTUD1 Ang II deubiquitination enzyme CDK9 

分 类 号：R692[医药卫生—泌尿科学]