Time course of pathogenic and adaptation mechanisms in cystinotic mouse kidneys

J Am Soc Nephrol. 2014 Jun;25(6):1256-69. doi: 10.1681/ASN.2013060598. Epub 2014 Feb 13.


Cystinosis, a main cause of Fanconi syndrome, is reproduced in congenic C57BL/6 cystinosin knockout (KO) mice. To identify the sequence of pathogenic and adaptation mechanisms of nephropathic cystinosis, we defined the onset of Fanconi syndrome in KO mice between 3 and 6 months of age and analyzed the correlation with structural and functional changes in proximal tubular cells (PTCs), with focus on endocytosis of ultrafiltrated disulfide-rich proteins as a key source of cystine. Despite considerable variation between mice at the same age, typical event sequences were delineated. At the cellular level, amorphous lysosomal inclusions preceded cystine crystals and eventual atrophy without crystals. At the nephron level, lesions started at the glomerulotubular junction and then extended distally. In situ hybridization and immunofluorescence revealed progressive loss of expression of megalin, cubilin, sodium-glucose cotransporter 2, and type IIa sodium-dependent phosphate cotransporter, suggesting apical dedifferentiation accounting for Fanconi syndrome before atrophy. Injection of labeled proteins revealed that defective endocytosis in S1 PTCs led to partial compensatory uptake by S3 PTCs, suggesting displacement of endocytic load and injury by disulfide-rich cargo. Increased PTC apoptosis allowed luminal shedding of cystine crystals and was partially compensated for by tubular proliferation. We conclude that lysosomal storage triggered by soluble cystine accumulation induces apical PTC dedifferentiation, which causes transfer of the harmful load of disulfide-rich proteins to more distal cells, possibly explaining longitudinal progression of swan-neck lesions. Furthermore, our results suggest that subsequent adaptation mechanisms include lysosomal clearance of free and crystalline cystine into urine and ongoing tissue repair.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Physiological / physiology*
  • Amino Acid Transport Systems, Neutral / genetics*
  • Animals
  • Apoptosis / physiology
  • Cell Proliferation
  • Crystallization
  • Cystine / chemistry
  • Cystine / metabolism
  • Cystinosis / genetics
  • Cystinosis / pathology
  • Cystinosis / physiopathology*
  • Disease Models, Animal
  • Disease Progression
  • Endocytosis / physiology
  • Fanconi Syndrome / genetics
  • Fanconi Syndrome / pathology
  • Fanconi Syndrome / physiopathology*
  • Kidney Tubules, Proximal / pathology
  • Kidney Tubules, Proximal / physiology
  • Kidney Tubules, Proximal / physiopathology*
  • Low Density Lipoprotein Receptor-Related Protein-2 / genetics
  • Lysosomes / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Proteinuria / genetics
  • Proteinuria / pathology
  • Proteinuria / physiopathology
  • Receptors, Cell Surface / genetics
  • Vacuoles / pathology


  • Amino Acid Transport Systems, Neutral
  • Low Density Lipoprotein Receptor-Related Protein-2
  • Lrp2 protein, mouse
  • Receptors, Cell Surface
  • cystinosin protein, mouse
  • intrinsic factor-cobalamin receptor
  • Cystine