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Dedifferentiation and aberrations of the endolysosomal compartment characterize the early stage of nephropathic cystinosis


Raggi, Claudia; Luciani, Alessandro; Nevo, Nathalie; Antignac, Corinne; Terryn, Sara; Devuyst, Olivier (2014). Dedifferentiation and aberrations of the endolysosomal compartment characterize the early stage of nephropathic cystinosis. Human Molecular Genetics, 23(9):2266-2278.

Abstract

Nephropathic cystinosis, a lysosomal storage disease caused by mutations in the CTNS gene encoding the lysosomal cystine transporter cystinosin, is characterized by generalized proximal tubule dysfunction that progresses, if untreated, to end-stage renal disease. The pathogenesis of defective proximal tubule cellular transport in nephropathic cystinosis remains unclear. We characterized a recently generated line of C57BL/6 Ctns mice and analyzed endocytic uptake, lysosome function, and dedifferentiation and proliferation markers using primary cultures of proximal tubule epithelial cells derived from Ctns(-/-) and Ctns(+/+) littermates. Metabolic studies revealed that Ctns(-/-) mice show a progressive proximal tubule dysfunction characterized by low-molecular-weight proteinuria, glucosuria and phosphaturia, before structural damage and in absence of renal failure. These changes are related to decreased expression of the multi-ligand receptors megalin and cubilin and to increased dedifferentiation (ZONAB transcription factor) and proliferation (PCNA and Cyclin D1) rates. Studies on proximal tubule cells derived from Ctns(-/-) kidneys confirmed cystine overload, with accumulation of enlarged, dysfunctional lysosomes and reduced expression of endocytic receptors reflected by decreased uptake of specific ligands. These changes were related to a loss of integrity of tight junctions with a nuclear translocation of ZONAB and increased proliferation, as observed in Ctns(-/-) kidneys. These data reveal that the absence of cystinosin in proximal tubule cells triggers aberrations of the endolysosomal compartment, transport defects and an abnormal transcription program in the early stage of nephropathic cystinosis. Insights into the early manifestations of cystinosis may offer new targets for intervention, before irreversible renal damage.

Abstract

Nephropathic cystinosis, a lysosomal storage disease caused by mutations in the CTNS gene encoding the lysosomal cystine transporter cystinosin, is characterized by generalized proximal tubule dysfunction that progresses, if untreated, to end-stage renal disease. The pathogenesis of defective proximal tubule cellular transport in nephropathic cystinosis remains unclear. We characterized a recently generated line of C57BL/6 Ctns mice and analyzed endocytic uptake, lysosome function, and dedifferentiation and proliferation markers using primary cultures of proximal tubule epithelial cells derived from Ctns(-/-) and Ctns(+/+) littermates. Metabolic studies revealed that Ctns(-/-) mice show a progressive proximal tubule dysfunction characterized by low-molecular-weight proteinuria, glucosuria and phosphaturia, before structural damage and in absence of renal failure. These changes are related to decreased expression of the multi-ligand receptors megalin and cubilin and to increased dedifferentiation (ZONAB transcription factor) and proliferation (PCNA and Cyclin D1) rates. Studies on proximal tubule cells derived from Ctns(-/-) kidneys confirmed cystine overload, with accumulation of enlarged, dysfunctional lysosomes and reduced expression of endocytic receptors reflected by decreased uptake of specific ligands. These changes were related to a loss of integrity of tight junctions with a nuclear translocation of ZONAB and increased proliferation, as observed in Ctns(-/-) kidneys. These data reveal that the absence of cystinosin in proximal tubule cells triggers aberrations of the endolysosomal compartment, transport defects and an abnormal transcription program in the early stage of nephropathic cystinosis. Insights into the early manifestations of cystinosis may offer new targets for intervention, before irreversible renal damage.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology

04 Faculty of Medicine > Center for Integrative Human Physiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2014
Deposited On:19 Dec 2013 12:35
Last Modified:21 Nov 2017 17:00
Publisher:Oxford University Press
ISSN:0964-6906
Additional Information:This is a pre-copy-editing, author-produced PDF of an article accepted for publication in Human Molecular Genetics following peer review. The definitive publisher-authenticated version Raggi, Claudia; Luciani, Alessandro; Nevo, Nathalie; Antignac, Corinne; Terryn, Sara; Devuyst, Olivier (2013). Dedifferentiation and aberrations of the endolysosomal compartment characterize the early stage of nephropathic cystinosis. Human Molecular Genetics:Epub ahead of print. is available online at: http://hmg.oxfordjournals.org/content/early/2013/12/05/hmg.ddt617
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1093/hmg/ddt617
PubMed ID:24319100

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