Anoctamin 1 Inhibition Suppresses Cystogenesis by Enhancing Ciliogenesis and the Ciliary Dosage of Polycystins

Tao Xu; Meihan Chen; Qingwen Xu; Cheng Xue; Lili Fu; Kun Ling; Jinghua Hu; Changlin Mei

doi:10.31083/j.fbl2707216

Anoctamin 1 Inhibition Suppresses Cystogenesis by Enhancing Ciliogenesis and the Ciliary Dosage of Polycystins

Tao Xu, Meihan Chen, Qingwen Xu, Cheng Xue, Lili Fu, Kun Ling, Jinghua Hu, Changlin Mei

Biochemistry and Molecular Biology

Research output: Contribution to journal › Article › peer-review

Abstract

Background: Autosomal dominant polycystic kidney disease (ADPKD) is a ciliopathy characterized by abnormal tubular epithelial proliferation and fluid secretion. Anoctamin 1 (ANO1) is a calcium-dependent chloride channel. However, how ANO1 contributes to ADPKD is largely unexplored. Methods: Kidney tissues from ADPKD patients, Pkd1^RC/RC mice model, WT9-7 human PKD1^+/− cells, and 3D culture models in vitro were used. Localization of ANO1 and cilium length were investigated by confocal immunofluorescence. Results: We found that ANO1 was consistently upregulated in human and mouse PKD kidneys. Intriguingly, ANO1 located in a vesicle-like pattern at the ciliary base but not on the ciliary surface. ANO1 deficiency enhanced ciliogenesis and the ciliary dosage of polycystin-2 in human PKD cells, and reduced cyst formation in 3D culture models. Moreover, inhibition of ANO1 abolished the activation of STAT3 and ERK pathways in PKD cells. Conclusions: Our data indicate ANO1 is a negative regulator for both cilia length and cilia trafficking of polycystin-2 and provide mechanistic insights regarding the therapeutic potential of ANO1 pathway in ADPKD treatment.

Original language	English (US)
Article number	216
Journal	Frontiers in Bioscience - Landmark
Volume	27
Issue number	7
DOIs	https://doi.org/10.31083/j.fbl2707216
State	Published - Jul 2022

Keywords

anoctamin 1
autosomal dominant polycystic kidney disease
polycystin
primary cilium

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)
Immunology and Microbiology(all)

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10.31083/j.fbl2707216

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@article{46a85fc490fe4984b6a87aede8aa33da,

title = "Anoctamin 1 Inhibition Suppresses Cystogenesis by Enhancing Ciliogenesis and the Ciliary Dosage of Polycystins",

abstract = "Background: Autosomal dominant polycystic kidney disease (ADPKD) is a ciliopathy characterized by abnormal tubular epithelial proliferation and fluid secretion. Anoctamin 1 (ANO1) is a calcium-dependent chloride channel. However, how ANO1 contributes to ADPKD is largely unexplored. Methods: Kidney tissues from ADPKD patients, Pkd1RC/RC mice model, WT9-7 human PKD1+/− cells, and 3D culture models in vitro were used. Localization of ANO1 and cilium length were investigated by confocal immunofluorescence. Results: We found that ANO1 was consistently upregulated in human and mouse PKD kidneys. Intriguingly, ANO1 located in a vesicle-like pattern at the ciliary base but not on the ciliary surface. ANO1 deficiency enhanced ciliogenesis and the ciliary dosage of polycystin-2 in human PKD cells, and reduced cyst formation in 3D culture models. Moreover, inhibition of ANO1 abolished the activation of STAT3 and ERK pathways in PKD cells. Conclusions: Our data indicate ANO1 is a negative regulator for both cilia length and cilia trafficking of polycystin-2 and provide mechanistic insights regarding the therapeutic potential of ANO1 pathway in ADPKD treatment.",

keywords = "anoctamin 1, autosomal dominant polycystic kidney disease, polycystin, primary cilium",

author = "Tao Xu and Meihan Chen and Qingwen Xu and Cheng Xue and Lili Fu and Kun Ling and Jinghua Hu and Changlin Mei",

note = "Funding Information: This study was supported by grants from the national key research and development program of china (2016yfc0901502), the national natural science foundation of china (no. 81873595, 81670612, 81300560), shanghai municipal key clinical specialty (shslczdzk02503) and pu-jiang talent program of shanghai, china (no. 17pj1407700). Publisher Copyright: {\textcopyright} 2022 Frontiers in Bioscience. All rights reserved.",

year = "2022",

month = jul,

doi = "10.31083/j.fbl2707216",

language = "English (US)",

volume = "27",

journal = "Frontiers in Bioscience - Landmark",

issn = "2768-6701",

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T1 - Anoctamin 1 Inhibition Suppresses Cystogenesis by Enhancing Ciliogenesis and the Ciliary Dosage of Polycystins

AU - Xu, Tao

AU - Chen, Meihan

AU - Xu, Qingwen

AU - Xue, Cheng

AU - Fu, Lili

AU - Ling, Kun

AU - Hu, Jinghua

AU - Mei, Changlin

N1 - Funding Information: This study was supported by grants from the national key research and development program of china (2016yfc0901502), the national natural science foundation of china (no. 81873595, 81670612, 81300560), shanghai municipal key clinical specialty (shslczdzk02503) and pu-jiang talent program of shanghai, china (no. 17pj1407700). Publisher Copyright: © 2022 Frontiers in Bioscience. All rights reserved.

PY - 2022/7

Y1 - 2022/7

N2 - Background: Autosomal dominant polycystic kidney disease (ADPKD) is a ciliopathy characterized by abnormal tubular epithelial proliferation and fluid secretion. Anoctamin 1 (ANO1) is a calcium-dependent chloride channel. However, how ANO1 contributes to ADPKD is largely unexplored. Methods: Kidney tissues from ADPKD patients, Pkd1RC/RC mice model, WT9-7 human PKD1+/− cells, and 3D culture models in vitro were used. Localization of ANO1 and cilium length were investigated by confocal immunofluorescence. Results: We found that ANO1 was consistently upregulated in human and mouse PKD kidneys. Intriguingly, ANO1 located in a vesicle-like pattern at the ciliary base but not on the ciliary surface. ANO1 deficiency enhanced ciliogenesis and the ciliary dosage of polycystin-2 in human PKD cells, and reduced cyst formation in 3D culture models. Moreover, inhibition of ANO1 abolished the activation of STAT3 and ERK pathways in PKD cells. Conclusions: Our data indicate ANO1 is a negative regulator for both cilia length and cilia trafficking of polycystin-2 and provide mechanistic insights regarding the therapeutic potential of ANO1 pathway in ADPKD treatment.

AB - Background: Autosomal dominant polycystic kidney disease (ADPKD) is a ciliopathy characterized by abnormal tubular epithelial proliferation and fluid secretion. Anoctamin 1 (ANO1) is a calcium-dependent chloride channel. However, how ANO1 contributes to ADPKD is largely unexplored. Methods: Kidney tissues from ADPKD patients, Pkd1RC/RC mice model, WT9-7 human PKD1+/− cells, and 3D culture models in vitro were used. Localization of ANO1 and cilium length were investigated by confocal immunofluorescence. Results: We found that ANO1 was consistently upregulated in human and mouse PKD kidneys. Intriguingly, ANO1 located in a vesicle-like pattern at the ciliary base but not on the ciliary surface. ANO1 deficiency enhanced ciliogenesis and the ciliary dosage of polycystin-2 in human PKD cells, and reduced cyst formation in 3D culture models. Moreover, inhibition of ANO1 abolished the activation of STAT3 and ERK pathways in PKD cells. Conclusions: Our data indicate ANO1 is a negative regulator for both cilia length and cilia trafficking of polycystin-2 and provide mechanistic insights regarding the therapeutic potential of ANO1 pathway in ADPKD treatment.

KW - anoctamin 1

KW - autosomal dominant polycystic kidney disease

KW - polycystin

KW - primary cilium

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Anoctamin 1 Inhibition Suppresses Cystogenesis by Enhancing Ciliogenesis and the Ciliary Dosage of Polycystins

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