Protection of Cystinotic Mice by Kidney-Specific Megalin Ablation Supports an Endocytosis-Based Mechanism for Nephropathic Cystinosis Progression

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  • Virginie Janssens, Cell Biology Unit, de Duve Institute and Université Catholique de Louvain, Brussels, Belgium.
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  • Héloïse P Gaide Chevronnay, Cell Biology Unit, de Duve Institute and Université Catholique de Louvain, Brussels, Belgium.
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  • Sandrine Marie, Biochemical Genetics, Academic Hospital Saint-Luc, Brussels, Belgium.
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  • Marie-Françoise Vincent, Biochemical Genetics, Academic Hospital Saint-Luc, Brussels, Belgium.
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  • Patrick Van Der Smissen, Cell Biology Unit, de Duve Institute and Université Catholique de Louvain, Brussels, Belgium.
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  • Nathalie Nevo, Laboratory of Hereditary Kidney Diseases, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Imagine Institute, Paris Descartes University, Paris, France.
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  • Seppo Vainio, Faculty of Biochemistry and Molecular Medicine, Laboratory of Developmental Biology, Oulu Center for Cell-Matrix Research, Biocenter Oulu, University of Oulu, Oulu, Finland.
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  • Rikke Nielsen
  • Erik I Christensen
  • François Jouret, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA), Cardiovascular Sciences, University of Liège, Liège, Belgium.
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  • Corinne Antignac, Laboratory of Hereditary Kidney Diseases, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Imagine Institute, Paris Descartes University, Paris, France.
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  • Christophe E Pierreux, Cell Biology Unit, de Duve Institute and Université Catholique de Louvain, Brussels, Belgium; christophe.pierreux@uclouvain.be.
  • ,
  • Pierre J Courtoy, Cell Biology Unit, de Duve Institute and Université Catholique de Louvain, Brussels, Belgium.

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.

OriginalsprogEngelsk
TidsskriftJournal of the American Society of Nephrology : JASN
Vol/bind30
Nummer11
Sider (fra-til)2177-2190
Antal sider14
ISSN1046-6673
DOI
StatusUdgivet - nov. 2019

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Copyright © 2019 by the American Society of Nephrology.

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