Therapeutic Potential for CFTR Correctors in Autosomal Recessive Polycystic Kidney DiseaseSummary

Background & Aims: Autosomal recessive polycystic kidney disease (ARPKD) is caused by mutations in PKHD1, encoding fibrocystin/polyductin (FPC). Severe disease occurs in perinates. Those who survive the neonatal period face a myriad of comorbidities, including systemic and portal hypertensio...

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Autores principales:	Murali K. Yanda, Vartika Tomar, Liudmila Cebotaru
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Processing Trafficking ARPKD FPC ERAD Diseases of the digestive system. Gastroenterology RC799-869
Acceso en línea:	https://doaj.org/article/e684dd6174c740629decf06a8b20f547
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spelling	oai:doaj.org-article:e684dd6174c740629decf06a8b20f5472021-11-12T04:39:14ZTherapeutic Potential for CFTR Correctors in Autosomal Recessive Polycystic Kidney DiseaseSummary2352-345X10.1016/j.jcmgh.2021.07.012https://doaj.org/article/e684dd6174c740629decf06a8b20f5472021-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2352345X21001582https://doaj.org/toc/2352-345XBackground & Aims: Autosomal recessive polycystic kidney disease (ARPKD) is caused by mutations in PKHD1, encoding fibrocystin/polyductin (FPC). Severe disease occurs in perinates. Those who survive the neonatal period face a myriad of comorbidities, including systemic and portal hypertension, liver fibrosis, and hepatosplenomegaly. The goal here was to uncover therapeutic strategies for ARPKD. Methods: We used wild-type and an FPC-mutant cholangiocyte cell line in 3-dimenional cysts and in confluent monolayers to evaluate protein expression using western blotting and protein trafficking using confocal microscopy. Results: We found that the protein level of the cystic fibrosis transmembrane conductance regulator (CFTR) was downregulated. The levels of heat shock proteins (HSPs) were altered in the FPC-mutant cholangiocytes, with HSP27 being downregulated and HSP90 and HSP70 upregulated. FPC-mutant cholangiocytes formed cysts, but normal cells did not. Cyst growth could be reduced by increasing HSP27 protein levels, by HSP90 and HSP70 inhibitor treatments, by silencing HSP90 through messenger RNA inhibition, or by the novel approach of treating the cysts with the CFTR corrector VX-809. In wild-type cholangiocytes, CFTR is present in both apical and basolateral membranes. FPC malfunction resulted in altered colocalization of CFTR with both apical and basolateral membranes. Whereas, treatment with VX-809, increasing HSP27 or inhibiting HSP70 or HSP90 restored CFTR localization toward normal values. Conclusions: FPC malfunction induces the formation of cysts, which are fueled by alterations in HSPs and in CFTR protein levels and miss-localization. We suggest that CFTR correctors, already in clinical use to treat cystic fibrosis, could also be used as a treatment for ARPKD.Murali K. YandaVartika TomarLiudmila CebotaruElsevierarticleProcessingTraffickingARPKDFPCERADDiseases of the digestive system. GastroenterologyRC799-869ENCellular and Molecular Gastroenterology and Hepatology, Vol 12, Iss 5, Pp 1517-1529 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Processing Trafficking ARPKD FPC ERAD Diseases of the digestive system. Gastroenterology RC799-869
spellingShingle	Processing Trafficking ARPKD FPC ERAD Diseases of the digestive system. Gastroenterology RC799-869 Murali K. Yanda Vartika Tomar Liudmila Cebotaru Therapeutic Potential for CFTR Correctors in Autosomal Recessive Polycystic Kidney DiseaseSummary
description	Background & Aims: Autosomal recessive polycystic kidney disease (ARPKD) is caused by mutations in PKHD1, encoding fibrocystin/polyductin (FPC). Severe disease occurs in perinates. Those who survive the neonatal period face a myriad of comorbidities, including systemic and portal hypertension, liver fibrosis, and hepatosplenomegaly. The goal here was to uncover therapeutic strategies for ARPKD. Methods: We used wild-type and an FPC-mutant cholangiocyte cell line in 3-dimenional cysts and in confluent monolayers to evaluate protein expression using western blotting and protein trafficking using confocal microscopy. Results: We found that the protein level of the cystic fibrosis transmembrane conductance regulator (CFTR) was downregulated. The levels of heat shock proteins (HSPs) were altered in the FPC-mutant cholangiocytes, with HSP27 being downregulated and HSP90 and HSP70 upregulated. FPC-mutant cholangiocytes formed cysts, but normal cells did not. Cyst growth could be reduced by increasing HSP27 protein levels, by HSP90 and HSP70 inhibitor treatments, by silencing HSP90 through messenger RNA inhibition, or by the novel approach of treating the cysts with the CFTR corrector VX-809. In wild-type cholangiocytes, CFTR is present in both apical and basolateral membranes. FPC malfunction resulted in altered colocalization of CFTR with both apical and basolateral membranes. Whereas, treatment with VX-809, increasing HSP27 or inhibiting HSP70 or HSP90 restored CFTR localization toward normal values. Conclusions: FPC malfunction induces the formation of cysts, which are fueled by alterations in HSPs and in CFTR protein levels and miss-localization. We suggest that CFTR correctors, already in clinical use to treat cystic fibrosis, could also be used as a treatment for ARPKD.
format	article
author	Murali K. Yanda Vartika Tomar Liudmila Cebotaru
author_facet	Murali K. Yanda Vartika Tomar Liudmila Cebotaru
author_sort	Murali K. Yanda
title	Therapeutic Potential for CFTR Correctors in Autosomal Recessive Polycystic Kidney DiseaseSummary
title_short	Therapeutic Potential for CFTR Correctors in Autosomal Recessive Polycystic Kidney DiseaseSummary
title_full	Therapeutic Potential for CFTR Correctors in Autosomal Recessive Polycystic Kidney DiseaseSummary
title_fullStr	Therapeutic Potential for CFTR Correctors in Autosomal Recessive Polycystic Kidney DiseaseSummary
title_full_unstemmed	Therapeutic Potential for CFTR Correctors in Autosomal Recessive Polycystic Kidney DiseaseSummary
title_sort	therapeutic potential for cftr correctors in autosomal recessive polycystic kidney diseasesummary
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/e684dd6174c740629decf06a8b20f547
work_keys_str_mv	AT muralikyanda therapeuticpotentialforcftrcorrectorsinautosomalrecessivepolycystickidneydiseasesummary AT vartikatomar therapeuticpotentialforcftrcorrectorsinautosomalrecessivepolycystickidneydiseasesummary AT liudmilacebotaru therapeuticpotentialforcftrcorrectorsinautosomalrecessivepolycystickidneydiseasesummary
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Therapeutic Potential for CFTR Correctors in Autosomal Recessive Polycystic Kidney DiseaseSummary

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