4-Phenylbutyric Acid Treatment Reduces Low-Molecular-Weight Proteinuria in a Clcn5 Knock-in Mouse Model for Dent Disease-1

Author:

Perdomo-Ramírez Ana1ORCID,Ramos-Trujillo Elena12,Machado Jose David2,García-Nieto Victor3,Mura-Escorche Glorián1,Claverie-Martin Félix1ORCID

Affiliation:

1. Unidad de Investigacion, Hospital Universitario Nuestra Señora de Candelaria, Instituto de Investigacion Sanitaria de Canarias (IISC), 38010 Santa Cruz de Tenerife, Spain

2. Seccion Medicina, Departamento de Medicina Fisica y Farmacologia, Facultad de Ciencias de la Salud, Universidad de La Laguna, 38200 Santa Cruz de Tenerife, Spain

3. Unidad de Nefrologia Pediatrica, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain

Abstract

Dent disease-1 (DD-1) is a rare X-linked tubular disorder characterized by low-molecular-weight proteinuria (LMWP), hypercalciuria, nephrolithiasis and nephrocalcinosis. This disease is caused by inactivating mutations in the CLCN5 gene which encodes the voltage-gated ClC-5 chloride/proton antiporter. Currently, the treatment of DD-1 is only supportive and focused on delaying the progression of the disease. Here, we generated and characterized a Clcn5 knock-in mouse model that carries a pathogenic CLCN5 variant, c. 1566_1568delTGT; p.Val523del, which has been previously detected in several DD-1 unrelated patients, and presents the main clinical manifestations of DD-1 such as high levels of urinary b2-microglobulin, phosphate and calcium. Mutation p.Val523del causes partial ClC-5 retention in the endoplasmic reticulum. Additionally, we assessed the ability of sodium 4-phenylbutyrate, a small chemical chaperone, to ameliorate DD-1 symptoms in this mouse model. The proposed model would be of significant value in the investigation of the fundamental pathological processes underlying DD-1 and in the development of effective therapeutic strategies for this rare condition.

Funder

Asociacion de la Enfermedad de Dent

Instituto de Salud Carlos III

Universidad de La Laguna

Publisher

MDPI AG

Reference67 articles.

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