Frontiers in bioscience (Landmark edition) · 2022
Anoctamin 1 Inhibition Suppresses Cystogenesis by Enhancing Ciliogenesis and the Ciliary Dosage of Polycystins.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Xu Tao, Chen Meihan, Xu Qingwen, Xue Cheng, Fu Lili, Ling Kun, Hu Jinghua, Mei Changlin
Аннотация
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.
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.