title: Endo-lysosomal dysfunction in human proximal tubular epithelial cells deficient for lysosomal cystine transporter cystinosin.
abstract: Nephropathic cystinosis is a lysosomal storage disorder caused by mutations in the CTNS gene encoding cystine transporter cystinosin that results in accumulation of amino acid cystine in the lysosomes throughout the body and especially affects kidneys. Early manifestations of the disease include renal Fanconi syndrome, a generalized proximal tubular dysfunction. Current therapy of cystinosis is based on cystine-lowering drug cysteamine that postpones the disease progression but offers no cure for the Fanconi syndrome. We studied the mechanisms of impaired reabsorption in human proximal tubular epithelial cells (PTEC) deficient for cystinosin and investigated the endo-lysosomal compartments of cystinosin-deficient PTEC by means of light and electron microscopy. We demonstrate that cystinosin-deficient cells had abnormal shape and distribution of the endo-lysosomal compartments and impaired endocytosis, with decreased surface expression of multiligand receptors and delayed lysosomal cargo processing. Treatment with cysteamine improved surface expression and lysosomal cargo processing but did not lead to a complete restoration and had no effect on the abnormal morphology of endo-lysosomal compartments. The obtained results improve our understanding of the mechanism of proximal tubular dysfunction in cystinosis and indicate that impaired protein reabsorption can, at least partially, be explained by abnormal trafficking of endosomal vesicles.
authors: Department of Pediatric Nephrology & Growth and Regeneration, University Hospitals Leuven & Katholieke Universiteit, Leuven, Belgium.
authors: Ekaterina A
authors: EA
authors: Ivanova
authors: Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy.
authors: Maria Giovanna
authors: MG
authors: De Leo
authors: Department of Pediatric Nephrology & Growth and Regeneration, University Hospitals Leuven & Katholieke Universiteit, Leuven, Belgium; Department of Pediatric Nephrology, Radboud University Medical Center Nijmegen, Nijmegen, The Netherlands.
authors: Lambertus
authors: L
authors: Van Den Heuvel
authors: Laboratory of Proteomics and Metabolomics, Children's Hospital and Research Institute "Bambino Gesù" IRCCS, Rome, Italy.
authors: Anna
authors: A
authors: Pastore
authors: Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors: Henry
authors: H
authors: Dijkman
authors: Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy.
authors: Maria Antonietta
authors: MA
authors: De Matteis
authors: Department of Pediatric Nephrology & Growth and Regeneration, University Hospitals Leuven & Katholieke Universiteit, Leuven, Belgium.
authors: Elena N
authors: EN
authors: Levtchenko
mesh_terms: D026921:Amino Acid Transport Systems, Neutral / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism* / Q000648:ultrastructure; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology* / Q000378:metabolism*; D016547:Kinesins / Q000378:metabolism; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000235:genetics / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D014176:Protein Biosynthesis
chemical_list: D026921:Amino Acid Transport Systems, Neutral; C111445:CTNS protein, human; C488101:KIF5B protein, human; D026561:Low Density Lipoprotein Receptor-Related Protein-2; D016547:Kinesins