A novel transgenic mouse model highlights molecular disruptions involved in the pathogenesis of Dent disease 1.
Détails
ID Serval
serval:BIB_4461B27B4381
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
A novel transgenic mouse model highlights molecular disruptions involved in the pathogenesis of Dent disease 1.
Périodique
Gene
ISSN
1879-0038 (Electronic)
ISSN-L
0378-1119
Statut éditorial
Publié
Date de publication
30/11/2024
Peer-reviewed
Oui
Volume
928
Pages
148766
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Publication Status: ppublish
Résumé
Dent disease (DD) is a hereditary renal disorder characterized by low molecular weight (LMW) proteinuria and progressive renal failure. Inactivating mutations of the CLCN5 gene encoding the 2Cl <sup>-</sup> /H <sup>+</sup> exchanger ClC-5 have been identified in patients with DD type 1. ClC-5 is essentially expressed in proximal tubules (PT) where it is thought to play a role in maintaining an efficient endocytosis of LMW proteins. However, the exact pathological roles of ClC-5 in progressive dysfunctions observed in DD type 1 are still unclear. To address this issue, we designed a mouse model carrying the most representative type of ClC-5 missense mutations found in DD patients. These mice showed a characteristic DD type 1 phenotype accompanied by altered endo-lysosomal system and autophagy functions. With ageing, KI mice showed increased renal fibrosis, apoptosis and major changes in cell metabolic functions as already suggested in previous DD models. Furthermore, we made the interesting new discovery that the Lipocalin-2-24p3R pathway might be involved in the progression of the disease. These results suggest a crosstalk between the proximal and distal nephron in the pathogenesis mechanisms involved in DD with an initial PT impairment followed by the Lipocalin-2 internalisation and 24p3R overexpression in more distal segments of the nephron. This first animal model of DD carrying a pathogenic mutation of Clcn5 and our findings pave the way aimed at exploring therapeutic strategies to limit the consequences of ClC-5 disruption in patients with DD type 1 developing chronic kidney disease.
Mots-clé
Animals, Chloride Channels/genetics, Chloride Channels/metabolism, Mice, Disease Models, Animal, Mice, Transgenic, Dent Disease/genetics, Kidney Tubules, Proximal/metabolism, Kidney Tubules, Proximal/pathology, Mutation, Missense, Humans, Lipocalin-2/genetics, Lipocalin-2/metabolism, Autophagy/genetics, Apoptosis/genetics, Genetic Diseases, X-Linked, Nephrolithiasis, ClC-5, Dent disease, Endocytosis, Lipcalin-2, Proximal tubule, Tissue damage
Pubmed
Web of science
Création de la notice
19/07/2024 14:10
Dernière modification de la notice
27/08/2024 7:19