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Protection of Cystinotic Mice by Kidney-Specific Megalin Ablation Supports an Endocytosis-Based Mechanism for
Virginie Janssens1, Héloïse P Gaide Chevronnay1, Sandrine Marie2
1Cell 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.
Insights
Blocking the megalin/LRP2 pathway in cystinotic mice prevents cystine accumulation in kidney cells. This finding highlights the pathway
Area of Science:
- Nephrology and Genetic Metabolic Disorders
- Cell Biology and Receptor-Mediated Transport
Background:
- Nephropathic cystinosis, caused by CTNS gene mutations, leads to cystine buildup in lysosomes, causing kidney damage and Fanconi syndrome.
- Current treatments like cysteamine manage cystine levels but are not curative, and the source of cystine accumulation remains unclear.
Purpose of the Study:
- To determine if the megalin/LRP2 receptor-mediated endocytosis pathway contributes to cystine accumulation in proximal tubular cells.
- To investigate the megalin/LRP2 pathway as a potential therapeutic target for nephropathic cystinosis.
Main Methods:
- Utilized a mouse model of cystinosis with conditional megalin/LRP2 gene deletion in proximal tubular cells via a Wnt4-CRE system.
- Assessed kidney cystine levels, crystal deposition, histopathology (swan-neck lesions, cell turnover), and expression of NaPi-IIa and SGLT-2 transporters.
Main Results:
- Megalin/LRP2 ablation in cystinotic mice significantly reduced kidney cystine accumulation and prevented lysosomal abnormalities and crystal formation.
- The treatment largely prevented swan-neck lesions, normalized proximal tubular cell turnover, and preserved apical expression of key transporters.
Conclusions:
- The megalin/LRP2 pathway plays a critical role in the progression of nephropathic cystinosis by mediating cystine uptake.
- Targeting the megalin/LRP2 pathway offers a promising therapeutic strategy for treating nephropathic cystinosis.
