title: Cystic fibrosis is associated with a defect in apical receptor-mediated endocytosis in mouse and human kidney.
abstract: Inactivation of the chloride channel cystic fibrosis transmembrane conductance regulator (CFTR) causes cystic fibrosis (CF). Although CFTR is expressed in the kidney, no overwhelming renal phenotype has been documented in patients with CF. This study investigated the expression, subcellular distribution, and processing of CFTR in the kidney; used various mouse models to assess the role of CFTR in proximal tubule (PT) endocytosis; and tested the relevance of these findings in patients with CF. The level of CFTR mRNA in mouse kidney approached that found in lung. CFTR was located in the apical area of PT cells, with a maximal intensity in the straight part (S3) of the PT. Fractionation showed that CFTR co-distributed with the chloride/proton exchanger ClC-5 in PT endosomes. Cftr(-/-) mice showed impaired (125)I-beta(2)-microglobulin uptake, together with a decreased amount of the multiligand receptor cubilin in the S3 segment and a significant loss of cubilin and its low molecular weight (LMW) ligands into the urine. Defective receptor-mediated endocytosis was found less consistently in Cftr(DeltaF/DeltaF) mice, characterized by a large phenotypic heterogeneity and moderate versus mice that lacked ClC-5. A significant LMW proteinuria (and particularly transferrinuria) also was documented in a cohort of patients with CF but not in patients with asthma and chronic lung inflammation. In conclusion, CFTR inactivation leads to a moderate defect in receptor-mediated PT endocytosis, associated with a cubilin defect and a significant LMW proteinuria in mouse and human. The magnitude of the endocytosis defect that is caused by CFTR versus ClC-5 loss likely reflects functional heterogeneity along the PT.
authors.affiliation: Division of Nephrology, Université catholique de Louvain, 10 Avenue Hippocrate, B-1200 Brussels, Belgium.
authors.forename: François
authors.initials: F
authors.lastname: Jouret
authors.forename: Alfred
authors.initials: A
authors.lastname: Bernard
authors.forename: Cédric
authors.initials: C
authors.lastname: Hermans
authors.forename: Geneviève
authors.initials: G
authors.lastname: Dom
authors.forename: Sara
authors.initials: S
authors.lastname: Terryn
authors.forename: Teresinha
authors.initials: T
authors.lastname: Leal
authors.forename: Patrick
authors.initials: P
authors.lastname: Lebecque
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Cassiman
authors.forename: Bob J
authors.initials: BJ
authors.lastname: Scholte
authors.forename: Hugo R
authors.initials: HR
authors.lastname: de Jonge
authors.forename: Pierre J
authors.initials: PJ
authors.lastname: Courtoy
authors.forename: Olivier
authors.initials: O
authors.lastname: Devuyst
mesh_terms: D000818:Animals; D001249:Asthma / Q000503:physiopathology; D018118:Chloride Channels / Q000378:metabolism*; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004705:Endocytosis / Q000502:physiology*; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D011507:Proteinuria / Q000175:diagnosis / Q000209:etiology; D012333:RNA, Messenger / Q000032:analysis; D011956:Receptors, Cell Surface / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D001613:beta 2-Microglobulin / Q000378:metabolism
chemical_list: C097503:CLC-5 chloride channel; D018118:Chloride Channels; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D001613:beta 2-Microglobulin; C029486:intrinsic factor-cobalamin receptor; D019005:Cystic Fibrosis Transmembrane Conductance Regulator