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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cystine / metabolism
  • Cystinosis / etiology*
  • Cystinosis / prevention & control
  • Disease Progression
  • Endocytosis*
  • Kidney Tubules, Proximal / pathology*
  • Low Density Lipoprotein Receptor-Related Protein-2 / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Signal Transduction / physiology
  • Wnt4 Protein / physiology


  • Low Density Lipoprotein Receptor-Related Protein-2
  • Lrp2 protein, mouse
  • Wnt4 Protein
  • Wnt4 protein, mouse
  • Cystine