Article (Scientific journals)
Protection of Cystinotic Mice by Kidney-Specific Megalin Ablation Supports an Endocytosis-Based Mechanism for Nephropathic Cystinosis Progression.
Janssens, Virginie; Gaide Chevronnay, Heloise P.; Marie, Sandrine et al.
2019In Journal of the American Society of Nephrology : JASN
Peer reviewed
 

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Keywords :
cystinosis; endocytosis; megalin; pathophysiology; renal proximal tubule cell
Abstract :
[en] BACKGROUND: Deletions or inactivating mutations of the cystinosin gene CTNS lead to cystine accumulation and crystals at acidic pH in patients with nephropathic cystinosis, a rare lysosomal storage disease and the main cause of hereditary renal Fanconi syndrome. Early use of oral cysteamine to prevent cystine accumulation slows progression of nephropathic cystinosis but it is a demanding treatment and not a cure. The source of cystine accumulating in kidney proximal tubular cells and cystine's role in disease progression are unknown. METHODS: To investigate whether receptor-mediated endocytosis by the megalin/LRP2 pathway of ultrafiltrated, disulfide-rich plasma proteins could be a source of cystine in proximal tubular cells, we used a mouse model of cystinosis in which conditional excision of floxed megalin/LRP2 alleles in proximal tubular cells of cystinotic mice was achieved by a Cre-LoxP strategy using Wnt4-CRE. We evaluated mice aged 6-9 months for kidney cystine levels and crystals; histopathology, with emphasis on swan-neck lesions and proximal-tubular-cell apoptosis and proliferation (turnover); and proximal-tubular-cell expression of the major apical transporters sodium-phosphate cotransporter 2A (NaPi-IIa) and sodium-glucose cotransporter-2 (SGLT-2). RESULTS: Wnt4-CRE-driven megalin/LRP2 ablation in cystinotic mice efficiently blocked kidney cystine accumulation, thereby preventing lysosomal deformations and crystal deposition in proximal tubular cells. Swan-neck lesions were largely prevented and proximal-tubular-cell turnover was normalized. Apical expression of the two cotransporters was also preserved. CONCLUSIONS: These observations support a key role of the megalin/LRP2 pathway in the progression of nephropathic cystinosis and provide a proof of concept for the pathway as a therapeutic target.
Disciplines :
Urology & nephrology
Author, co-author :
Janssens, Virginie
Gaide Chevronnay, Heloise P.
Marie, Sandrine
Vincent, Marie-Francoise
Van Der Smissen, Patrick
Nevo, Nathalie
Vainio, Seppo
Nielsen, Rikke
Christensen, Erik I.
Jouret, François  ;  Université de Liège - ULiège > Cardiovascular Sc.-Lab. of Translational Res. in Nephrology
Antignac, Corinne
Pierreux, Christophe E.
Courtoy, Pierre J.
More authors (3 more) Less
Language :
English
Title :
Protection of Cystinotic Mice by Kidney-Specific Megalin Ablation Supports an Endocytosis-Based Mechanism for Nephropathic Cystinosis Progression.
Publication date :
2019
Journal title :
Journal of the American Society of Nephrology : JASN
ISSN :
1046-6673
eISSN :
1533-3450
Peer reviewed :
Peer reviewed
Commentary :
Copyright (c) 2019 by the American Society of Nephrology.
Available on ORBi :
since 17 October 2019

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