期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 22, 期 16, 页码 -出版社
MDPI
DOI: 10.3390/ijms22169013
关键词
autosomal dominant polycystic kidney disease (ADPKD); cystic fibrosis transmembrane conductance regulator (CFTR); Kupffer's vesicle (KV); polycystin-2 (PC2)
资金
- Sociedade Portuguesa de Nefrologia by Fundacao para a Ciencia e Tecnologia (FCT)/Ministerio da Educacao e Ciencia [iNOVA4HealthUID/Multi/04462/2013]
- FEDER under the PT2020 Partnership Agreement)
- FCT
- iNOVA post-doctoral fellowship
- LYSOCIL project
- European Union [811087]
- research infrastructure Congento
- Lisboa Regional Operational Programme (Lisboa2020) under the PORTUGAL 2020 Partnership Agreement through the European Regional Development Fund (ERDF)
- FCT [LISBOA-01-0145-FEDER-022170]
- [FCT-ANR/BEX-BID/0153/2012]
- [PTDC/BEXBID/1411/2014]
This study demonstrates that knocking down PC2 affects CFTR-mediated inflation, with KV enlargement rescued by injection of Xenopus pkd2 mRNA and tolvaptan treatment. The findings support the use of KV as an in vivo model for screening compounds that may prevent cyst enlargement in ciliopathies through CFTR inhibition.
In autosomal dominant polycystic kidney disease (ADPKD), kidney cyst growth requires the recruitment of CFTR (cystic fibrosis transmembrane conductance regulator), the chloride channel that is defective in cystic fibrosis. We have been studying cyst inflation using the zebrafish Kupffer's vesicle (KV) as model system because we previously demonstrated that knocking down polycystin 2 (PC2) induced a CFTR-mediated enlargement of the organ. We have now quantified the PC2 knockdown by showing that it causes a 73% reduction in the number of KV cilia expressing PC2. According to the literature, this is an essential event in kidney cystogenesis in ADPKD mice. Additionally, we demonstrated that the PC2 knockdown leads to a significant accumulation of CFTR-GFP at the apical region of the KV cells. Furthermore, we determined that KV enlargement is rescued by the injection of Xenopus pkd2 mRNA and by 100 mu M tolvaptan treatment, the unique and approved pharmacologic approach for ADPKD management. We expected vasopressin V2 receptor antagonist to lower the cAMP levels of KV-lining cells and, thus, to inactivate CFTR. These findings further support the use of the KV as an in vivo model for screening compounds that may prevent cyst enlargement in this ciliopathy, through CFTR inhibition.
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