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

Meng-yang Wang1,2,3, Tian-xiang Yu1,2, Qin-yan Wang1,2, Xue Han1,2, Xiang Hu4, Shi-ju Ye2, Xiao-hong Long2, Yi Wang2, Hong Zhu4, Wu Luo2, Guang Liang1,2,5
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
Correspondence to: Wu Luo:, Guang Liang:,
DOI: 10.1038/s41401-023-01192-6
Received: 17 June 2023
Accepted: 5 November 2023
Advance online: 18 December 2023


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.

Keywords: hypertensive renal disease; OTUD1; Ang II; deubiquitination enzyme; CDK9

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