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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.

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



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.


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).


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.


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.


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

[Available on 2020-11-01]

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