title: Cystinosin deficiency causes podocyte damage and loss associated with increased cell motility.
abstract: The involvement of the glomerulus in the pathogenesis of cystinosis, caused by loss-of-function mutations in cystinosin (CTNS, 17p13), is a matter of controversy. Although patients with cystinosis demonstrate glomerular lesions and high-molecular-weight proteinuria starting from an early age, a mouse model of cystinosis develops only signs of proximal tubular dysfunction. Here we studied podocyte damage in patients with cystinosis by analyzing urinary podocyte excretion and by in vitro studies of podocytes deficient in cystinosin. Urine from patients with cystinosis presented a significantly higher amount of podocytes compared with controls. In culture, cystinotic podocytes accumulated cystine compatible with cystinosin deficiency. The expression of podocyte specific genes CD2AP, podocalyxin, and synaptopodin and of the WT1 protein was evident in all cell lines. Conditionally immortalized podocyte lines of 2 patients with different CTNS mutations had altered cytoskeleton, impaired cell adhesion sites, and increased individual cell motility. Moreover, these cells showed enhanced phosphorylation of both Akt1 and Akt2 (isoforms of protein kinase B). Inhibition of Akt by a specific inhibitor (Akti inhibitor 1/2) resulted in normalization of the hypermotile phenotype. Thus, our study extends the list of genetic disorders causing podocyte damage and provides the evidence of altered cell signaling cascades resulting in impaired cell adhesion and enhanced cell motility in cystinosis.
authors.affiliation: Department of Development and Regeneration, Laboratory of Pediatric Nephrology, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Ekaterina A
authors.initials: EA
authors.lastname: Ivanova
authors.affiliation: Department of Development and Regeneration, Laboratory of Pediatric Nephrology, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Fanny O
authors.initials: FO
authors.lastname: Arcolino
authors.affiliation: Department of Development and Regeneration, Laboratory of Pediatric Nephrology, Katholieke Universiteit Leuven, Leuven, Belgium; Department of Clinical and Chemical Pathology, Faculty of Medicine, Cairo University, Cairo, Egypt.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Elmonem
authors.affiliation: Renal Research Laboratory, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico and Fondazione D'Amico, Milano, Italy.
authors.forename: Maria P
authors.initials: MP
authors.lastname: Rastaldi
authors.affiliation: Renal Research Laboratory, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico and Fondazione D'Amico, Milano, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Giardino
authors.affiliation: Department of Pediatric Nephrology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: Cornelissen
authors.affiliation: Department of Development and Regeneration, Laboratory of Pediatric Nephrology, Katholieke Universiteit Leuven, Leuven, Belgium; Department of Pediatric Nephrology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Lambertus P
authors.initials: LP
authors.lastname: van den Heuvel
authors.affiliation: Department of Development and Regeneration, Laboratory of Pediatric Nephrology, Katholieke Universiteit Leuven, Leuven, Belgium. Electronic address: elena.levtchenko@uzleuven.be.
authors.forename: Elena N
authors.initials: EN
authors.lastname: Levtchenko
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D026921:Amino Acid Transport Systems, Neutral / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016022:Case-Control Studies; D002448:Cell Adhesion; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D003554:Cystinosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000652:urine; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D009154:Mutation; D010641:Phenotype; D010766:Phosphorylation; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D012795:Sialoglycoproteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014556:Urine / Q000166:cytology; D025721:WT1 Proteins / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D026921:Amino Acid Transport Systems, Neutral; C114545:CD2-associated protein; C111445:CTNS protein, human; D003598:Cytoskeletal Proteins; D047428:Protein Kinase Inhibitors; D012795:Sialoglycoproteins; D025721:WT1 Proteins; C583751:WT1 protein, human; C001643:podocalyxin; C494918:AKT1 protein, human; C494921:AKT2 protein, human; D051057:Proto-Oncogene Proteins c-akt
keywords: cell adhesion; cell motility; glomerular damage; nephropathic cystinosis; podocyturia