Defective CFTR leads to aberrant β-catenin activation and kidney fibrosis

Abstract Cystic fibrosis transmembrane conductance regulator (CFTR), known as a cAMP-activated Cl− channel, is widely expressed at the apical membrane of epithelial cells in a wide variety of tissues. Of note, despite the abundant expression of CFTR in mammalian kidney, the role of CFTR in kidney di...

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Autores principales:	Jie Ting Zhang, Yan Wang, Jun Jiang Chen, Xiao Hu Zhang, Jian Da Dong, Lai Ling Tsang, Xiao Ru Huang, Zhiming Cai, Hui Yao Lan, Xiao Hua Jiang, Hsiao Chang Chan
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/12e229d7fb814a3bb6c5e7916e428cd8
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spelling	oai:doaj.org-article:12e229d7fb814a3bb6c5e7916e428cd82021-12-02T11:52:57ZDefective CFTR leads to aberrant β-catenin activation and kidney fibrosis10.1038/s41598-017-05435-52045-2322https://doaj.org/article/12e229d7fb814a3bb6c5e7916e428cd82017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-05435-5https://doaj.org/toc/2045-2322Abstract Cystic fibrosis transmembrane conductance regulator (CFTR), known as a cAMP-activated Cl− channel, is widely expressed at the apical membrane of epithelial cells in a wide variety of tissues. Of note, despite the abundant expression of CFTR in mammalian kidney, the role of CFTR in kidney disease development is unclear. Here, we report that CFTR expression is downregulated in the UUO (unilateral ureteral obstruction)-induced kidney fibrosis mouse model and human fibrotic kidneys. Dysfunction or downregulation of CFTR in renal epithelial cells leads to alteration of genes involved in Epithelial-Mesenchymal Transition (EMT) and kidney fibrosis. In addition, dysregulation of CFTR activates canonical Wnt/β-catenin signaling pathways, whereas the β-catenin inhibitor reverses the effects of CFTR downregulation on EMT marker. More interestingly, CFTR interacts with Dishevelled 2 (Dvl2), a key component of Wnt signaling, thereby suppressing the activation of β-catenin. Compared to wild type, deltaF508 mice with UUO treatment exhibit significantly higher β-catenin activity with aggregated kidney fibrogenesis, which is reduced by forced overexpression of CFTR. Taken together, our study reveals a novel mechanism by which CFTR regulates Wnt/β-catenin signaling pertinent to progression of kidney fibrosis and indicates a potential treatment target.Jie Ting ZhangYan WangJun Jiang ChenXiao Hu ZhangJian Da DongLai Ling TsangXiao Ru HuangZhiming CaiHui Yao LanXiao Hua JiangHsiao Chang ChanNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jie Ting Zhang Yan Wang Jun Jiang Chen Xiao Hu Zhang Jian Da Dong Lai Ling Tsang Xiao Ru Huang Zhiming Cai Hui Yao Lan Xiao Hua Jiang Hsiao Chang Chan Defective CFTR leads to aberrant β-catenin activation and kidney fibrosis
description	Abstract Cystic fibrosis transmembrane conductance regulator (CFTR), known as a cAMP-activated Cl− channel, is widely expressed at the apical membrane of epithelial cells in a wide variety of tissues. Of note, despite the abundant expression of CFTR in mammalian kidney, the role of CFTR in kidney disease development is unclear. Here, we report that CFTR expression is downregulated in the UUO (unilateral ureteral obstruction)-induced kidney fibrosis mouse model and human fibrotic kidneys. Dysfunction or downregulation of CFTR in renal epithelial cells leads to alteration of genes involved in Epithelial-Mesenchymal Transition (EMT) and kidney fibrosis. In addition, dysregulation of CFTR activates canonical Wnt/β-catenin signaling pathways, whereas the β-catenin inhibitor reverses the effects of CFTR downregulation on EMT marker. More interestingly, CFTR interacts with Dishevelled 2 (Dvl2), a key component of Wnt signaling, thereby suppressing the activation of β-catenin. Compared to wild type, deltaF508 mice with UUO treatment exhibit significantly higher β-catenin activity with aggregated kidney fibrogenesis, which is reduced by forced overexpression of CFTR. Taken together, our study reveals a novel mechanism by which CFTR regulates Wnt/β-catenin signaling pertinent to progression of kidney fibrosis and indicates a potential treatment target.
format	article
author	Jie Ting Zhang Yan Wang Jun Jiang Chen Xiao Hu Zhang Jian Da Dong Lai Ling Tsang Xiao Ru Huang Zhiming Cai Hui Yao Lan Xiao Hua Jiang Hsiao Chang Chan
author_facet	Jie Ting Zhang Yan Wang Jun Jiang Chen Xiao Hu Zhang Jian Da Dong Lai Ling Tsang Xiao Ru Huang Zhiming Cai Hui Yao Lan Xiao Hua Jiang Hsiao Chang Chan
author_sort	Jie Ting Zhang
title	Defective CFTR leads to aberrant β-catenin activation and kidney fibrosis
title_short	Defective CFTR leads to aberrant β-catenin activation and kidney fibrosis
title_full	Defective CFTR leads to aberrant β-catenin activation and kidney fibrosis
title_fullStr	Defective CFTR leads to aberrant β-catenin activation and kidney fibrosis
title_full_unstemmed	Defective CFTR leads to aberrant β-catenin activation and kidney fibrosis
title_sort	defective cftr leads to aberrant β-catenin activation and kidney fibrosis
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/12e229d7fb814a3bb6c5e7916e428cd8
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_version_	1718394908449964032

Defective CFTR leads to aberrant β-catenin activation and kidney fibrosis

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