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Zebrafish Model as a Screen to Prevent Cyst Inflation in Autosomal Dominant Polycystic Kidney Disease

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 (K...

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Autores principales: Oliveira, Inês, Jacinto, Raquel, Pestana, Sara, Nolasco, Fernando, Calado, Joaquim, Lopes, Susana Santos, Roxo-Rosa, Mónica
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8396643/
https://www.ncbi.nlm.nih.gov/pubmed/34445719
http://dx.doi.org/10.3390/ijms22169013
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author Oliveira, Inês
Jacinto, Raquel
Pestana, Sara
Nolasco, Fernando
Calado, Joaquim
Lopes, Susana Santos
Roxo-Rosa, Mónica
author_facet Oliveira, Inês
Jacinto, Raquel
Pestana, Sara
Nolasco, Fernando
Calado, Joaquim
Lopes, Susana Santos
Roxo-Rosa, Mónica
author_sort Oliveira, Inês
collection PubMed
description 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 µM 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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spelling pubmed-83966432021-08-28 Zebrafish Model as a Screen to Prevent Cyst Inflation in Autosomal Dominant Polycystic Kidney Disease Oliveira, Inês Jacinto, Raquel Pestana, Sara Nolasco, Fernando Calado, Joaquim Lopes, Susana Santos Roxo-Rosa, Mónica Int J Mol Sci Article 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 µM 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. MDPI 2021-08-20 /pmc/articles/PMC8396643/ /pubmed/34445719 http://dx.doi.org/10.3390/ijms22169013 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Oliveira, Inês
Jacinto, Raquel
Pestana, Sara
Nolasco, Fernando
Calado, Joaquim
Lopes, Susana Santos
Roxo-Rosa, Mónica
Zebrafish Model as a Screen to Prevent Cyst Inflation in Autosomal Dominant Polycystic Kidney Disease
title Zebrafish Model as a Screen to Prevent Cyst Inflation in Autosomal Dominant Polycystic Kidney Disease
title_full Zebrafish Model as a Screen to Prevent Cyst Inflation in Autosomal Dominant Polycystic Kidney Disease
title_fullStr Zebrafish Model as a Screen to Prevent Cyst Inflation in Autosomal Dominant Polycystic Kidney Disease
title_full_unstemmed Zebrafish Model as a Screen to Prevent Cyst Inflation in Autosomal Dominant Polycystic Kidney Disease
title_short Zebrafish Model as a Screen to Prevent Cyst Inflation in Autosomal Dominant Polycystic Kidney Disease
title_sort zebrafish model as a screen to prevent cyst inflation in autosomal dominant polycystic kidney disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8396643/
https://www.ncbi.nlm.nih.gov/pubmed/34445719
http://dx.doi.org/10.3390/ijms22169013
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