ANOCTAMIN 1 抑制通过增强纤毛发生和多囊蛋白的纤毛剂量来抑制囊肿发生。

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

机构信息

Department of Nephrology, Shanghai Jiaotong University Medical School affiliated Shanghai Sixth People's Hospital, 200233 Shanghai, China.

Division of Nephrology, Kidney Institution of Chinese People's Liberation Army, Changzheng Hospital, 200003 Shanghai, China.

出版信息

Front Biosci (Landmark Ed). 2022 Jul 8;27(7):216. doi: 10.31083/j.fbl2707216.

DOI:10.31083/j.fbl2707216

PMID:35866397

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, mice model, WT9-7 human cells, and 3D culture models 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.

摘要

背景

常染色体显性多囊肾病（ADPKD）是一种纤毛病，其特征是管状上皮细胞异常增殖和液体分泌。ANO1（Anoctamin 1）是一种钙依赖性氯离子通道。然而，ANO1 如何导致 ADPKD 在很大程度上仍未被探索。

方法

使用 ADPKD 患者的肾脏组织、小鼠模型、WT9-7 人细胞和 3D 培养模型。通过共聚焦免疫荧光法研究 ANO1 和纤毛长度的定位。

结果

我们发现 ANO1 在人和小鼠 PKD 肾脏中持续上调。有趣的是，ANO1 位于纤毛基部的囊泡样模式中，而不在纤毛表面。ANO1 缺乏增强了人 PKD 细胞中的纤毛发生和多囊蛋白-2 的纤毛剂量，并减少了 3D 培养模型中的囊肿形成。此外，ANO1 的抑制消除了 PKD 细胞中 STAT3 和 ERK 途径的激活。