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J Am Soc Nephrol. 2019 Nov;30(11):2177-2190. doi: 10.1681/ASN.2019040371. Epub 2019 Sep 23.

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

Author information

1
Cell Biology Unit, de Duve Institute and Université Catholique de Louvain, Brussels, Belgium.
2
Biochemical Genetics, Academic Hospital Saint-Luc, Brussels, Belgium.
3
Laboratory of Hereditary Kidney Diseases, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Imagine Institute, Paris Descartes University, Paris, France.
4
Faculty of Biochemistry and Molecular Medicine, Laboratory of Developmental Biology, Oulu Center for Cell-Matrix Research, Biocenter Oulu, University of Oulu, Oulu, Finland.
5
Department of Biomedicine, Aarhus University, Aarhus, Denmark; and.
6
Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA), Cardiovascular Sciences, University of Liège, Liège, Belgium.
7
Cell Biology Unit, de Duve Institute and Université Catholique de Louvain, Brussels, Belgium; christophe.pierreux@uclouvain.be.

Abstract

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.

KEYWORDS:

cystinosis; endocytosis; megalin; pathophysiology; renal proximal tubule cell

PMID:
31548351
PMCID:
PMC6830792
[Available on 2020-11-01]
DOI:
10.1681/ASN.2019040371

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