Therapeutic Potential for CFTR Correctors in Autosomal Recessive Polycystic Kidney Disease.

Abstract

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.

• Authors: Murali K Yanda, Vartika Tomar, Liudmila Cebotaru
• Journal: Cellular and molecular gastroenterology and hepatology (Cell Mol Gastroenterol Hepatol) Vol. 12 Issue 5 Pg. 1517-1529 ( 2021) ISSN: 2352-345X [Electronic] United States
• PMID: 34329764 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• CFTR protein, human
• Heat-Shock Proteins
• PKHD1 protein, human
• Receptors, Cell Surface
• Cystic Fibrosis Transmembrane Conductance Regulator

Topics

• Animals
• Cell Line
• Cystic Fibrosis Transmembrane Conductance Regulator (genetics, metabolism)
• Disease Models, Animal
• Endoplasmic Reticulum-Associated Degradation
• Gene Expression Regulation
• Gene Silencing
• Genetic Predisposition to Disease
• Genetic Therapy (methods)
• Heat-Shock Proteins (genetics, metabolism)
• Humans
• Mice
• Mice, Knockout
• Mutation
• Phenotype
• Polycystic Kidney, Autosomal Recessive (diagnosis, genetics, metabolism, therapy)
• Protein Transport
• Receptors, Cell Surface (genetics, metabolism)
• Sequence Deletion