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.