Sp1-like protein KLF13 acts as a negative feedback regulator of TGF-β signaling and fibrosis

Shu Yang; Jiaqing Xiang; Chuanrui Ma; Guangyan Yang; Xinyu Wang; Hanyong Liu; Guanwei Fan; Lin Kang; Zhen Liang

Cell Reports (Apr 2023)

Sp1-like protein KLF13 acts as a negative feedback regulator of TGF-β signaling and fibrosis

Shu Yang,
Jiaqing Xiang,
Chuanrui Ma,
Guangyan Yang,
Xinyu Wang,
Hanyong Liu,
Guanwei Fan,
Lin Kang,
Zhen Liang

Affiliations

Shu Yang: Department of Geriatrics, The First Affiliated Hospital of Southern University of Science and Technology (Shenzhen People’s Hospital), Shenzhen, Guangdong 518020, China; Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong 518020, China; Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, China
Jiaqing Xiang: Department of Geriatrics, The First Affiliated Hospital of Southern University of Science and Technology (Shenzhen People’s Hospital), Shenzhen, Guangdong 518020, China; Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, China
Chuanrui Ma: First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China; Haihe Laboratory of Modern Chinese Medicine, Tianjin 301617, China
Guangyan Yang: Department of Geriatrics, The First Affiliated Hospital of Southern University of Science and Technology (Shenzhen People’s Hospital), Shenzhen, Guangdong 518020, China; Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong 518020, China; Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, China
Xinyu Wang: Department of Geriatrics, The First Affiliated Hospital of Southern University of Science and Technology (Shenzhen People’s Hospital), Shenzhen, Guangdong 518020, China; Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, China
Hanyong Liu: Department of Nephrology, The First Affiliated Hospital of Southern University of Science and Technology (Shenzhen People’s Hospital), Shenzhen, Guangdong 518020, China; Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, China
Guanwei Fan: First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China; Haihe Laboratory of Modern Chinese Medicine, Tianjin 301617, China; Corresponding author
Lin Kang: Department of Geriatrics, The First Affiliated Hospital of Southern University of Science and Technology (Shenzhen People’s Hospital), Shenzhen, Guangdong 518020, China; Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong 518020, China; The Biobank of National Innovation Center for Advanced Medical Devices, Shenzhen People’s Hospital, Shenzhen, Guangdong 518020, China; Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, China; Corresponding author
Zhen Liang: Department of Geriatrics, The First Affiliated Hospital of Southern University of Science and Technology (Shenzhen People’s Hospital), Shenzhen, Guangdong 518020, China; Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong 518020, China; Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, China; Corresponding author

Journal volume & issue: Vol. 42, no. 4
p. 112367

Abstract

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Summary: Transforming growth factor β (TGF-β) is the primary factor that drives fibrosis in most forms of chronic kidney disease. The aim of this study was to identify endogenous regulators of TGF-β signaling and fibrosis. Here, we show that tubulointerstitial fibrosis is aggravated by global deletion of KLF13 and attenuated by adeno-associated virus-mediated KLF13 overexpression in renal tubular epithelial cells. KLF13 recruits a repressor complex comprising SIN3A and histone deacetylase 1 (HDAC1) to the TGF-β target genes, limiting the profibrotic effects of TGF-β. Temporary upregulation of TGF-β induces KLF13 expression, creating a negative feedback loop that triggers the anti-fibrotic effect of KLF13. However, persistent activation of TGF-β signaling reduces KLF13 levels through FBXW7-mediated ubiquitination degradation and HDAC-dependent mechanisms to inhibit KLF13 transcription and offset the anti-fibrotic effect of KLF13. Collectively, our data demonstrate a role of KLF13 in regulating TGF-β signaling and fibrosis.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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