title: Time course of pathogenic and adaptation mechanisms in cystinotic mouse kidneys.
abstract: 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.
authors: Cell Biology Unit, de Duve Institute and Université Catholique de Louvain, Brussels, Belgium;
authors: Héloïse P
authors: HP
authors: Gaide Chevronnay
authors: Cell Biology Unit, de Duve Institute and Université Catholique de Louvain, Brussels, Belgium;
authors: Virginie
authors: V
authors: Janssens
authors: Cell Biology Unit, de Duve Institute and Université Catholique de Louvain, Brussels, Belgium;
authors: Patrick
authors: P
authors: Van Der Smissen
authors: Cell Biology Unit, de Duve Institute and Université Catholique de Louvain, Brussels, Belgium;
authors: Francisca
authors: F
authors: N'Kuli
authors: Inserm, U574, Hôpital Necker-Enfants Malades and Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Paris, France;
authors: Nathalie
authors: N
authors: Nevo
authors: Pathology Department, Saint-Luc University Clinics, Brussels, Belgium;
authors: Yves
authors: Y
authors: Guiot
authors: Department of Pediatric Nephrology, University Hospitals Leuven, Leuven, Belgium; and.
authors: Elena
authors: E
authors: Levtchenko
authors: Cell Biology Unit, de Duve Institute and Université Catholique de Louvain, Brussels, Belgium; Pathology Department, Saint-Luc University Clinics, Brussels, Belgium;
authors: Etienne
authors: E
authors: Marbaix
authors: Cell Biology Unit, de Duve Institute and Université Catholique de Louvain, Brussels, Belgium;
authors: Christophe E
authors: CE
authors: Pierreux
authors: Department of Pediatrics, Division of Genetics, University of California, San Diego, California.
authors: Stéphanie
authors: S
authors: Cherqui
authors: Inserm, U574, Hôpital Necker-Enfants Malades and Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Paris, France;
authors: Corinne
authors: C
authors: Antignac
authors: Cell Biology Unit, de Duve Institute and Université Catholique de Louvain, Brussels, Belgium;
authors: Pierre J
authors: PJ
authors: Courtoy
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology*; D026921:Amino Acid Transport Systems, Neutral / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D049109:Cell Proliferation; D003460:Crystallization; D003553:Cystine / Q000737:chemistry / Q000378:metabolism; D003554:Cystinosis / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D004705:Endocytosis / Q000502:physiology; D005198:Fanconi Syndrome / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D007687:Kidney Tubules, Proximal / Q000473:pathology / Q000502:physiology / Q000503:physiopathology*; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000235:genetics; D008247:Lysosomes / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011507:Proteinuria / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D011956:Receptors, Cell Surface / Q000235:genetics; D014617:Vacuoles / Q000473:pathology
chemical_list: D026921:Amino Acid Transport Systems, Neutral; D026561:Low Density Lipoprotein Receptor-Related Protein-2; C055127:Lrp2 protein, mouse; D011956:Receptors, Cell Surface; C534463:cystinosin protein, mouse; C029486:intrinsic factor-cobalamin receptor; D003553:Cystine