Journal
NEPHROLOGY DIALYSIS TRANSPLANTATION
Volume 25, Issue 4, Pages 1059-1066Publisher
OXFORD UNIV PRESS
DOI: 10.1093/ndt/gfp553
Keywords
chronic renal failure; cystinosis genetic background; mouse model; proximal tubule dysfunction
Categories
Funding
- Association pour l'Information et la Recherche sur les Maladies Renales Genetiques
- Cystinosis Research Foundation
- Vaincre les Maladies Lysosomales
- Cystinosis Research Network
- Belgian Fonds National de Is Recherche Scientifique and Fonds de la Recherche Scientifique Medicate
- Alphonse & Jean Forton Foundation
- Concerted Research Action [05/10-328]
- Inter-university Attraction Pole
- EUNEFRON [201590]
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Background. Cystinosis is caused by mutations in CTNS that encodes cystinosin, the lysosomal cystine transporter. The most severe and frequent form is characterized by a proximal tubulopathy that appears around 6 to 12 months of age. In the absence of treatment, end-stage renal disease is reached by 10 years. Ctns(-/-) mice of a mixed 129Sv x C57BL/6 genetic background show elevated renal cystine levels; however, proximal tubulopathy or end-stage renal disease is not observed. Methods. As renal phenotype can be influenced by genetic background, we generated congenic C57BL/6 and FVB/N Ctns(-/-) mice and assayed renal lesions and function by histological and biochemical studies. Results. C57BL/6 Ctns(-/-) mice showed significantly higher renal cystine levels than the FVB/N strain. Moreover, C57BL/6 mice presented with pronounced histological lesions of the proximal tubules as well as a tubulopathy and progressively developed chronic renal failure. In contrast, renal dysfunction was not observed in the FVB/N strain. Conclusions. Thus, the C57BL/6 strain represents the first Ctns(-/-) mouse model to show clear renal defects. In addition to highlighting the influence of genetic background on phenotype, the C57BL/6 Ctns(-/-) mice represent a useful model for further understanding cystinosin function in the kidney and, specifically, in the proximal tubules.
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