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|Title: ||Cystic fibrosis is associated with a defect in apical receptor-mediated endocytosis in mouse and human kidney|
|Authors: ||Jouret, Francois|
Scholte, Bob J.
de Jonge, Hugo R.
Courtoy, Pierre J.
|Issue Date: ||2007|
|Publisher: ||AMERICAN SOCIETY NEPHROLOGY|
|Citation: ||JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 18(3). p. 707-718|
|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 CIC-5 in PT endosomes. Cftr(-/-) mice showed impaired I-125-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(Delta F/Delta F) mice, characterized by a large phenotypic heterogeneity and moderate versus mice that lacked CIC-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 CIC-5 loss likely reflects functional heterogeneity along the PT.|
|Notes: ||Univ Catholique Louvain, Div Nephrol, B-1200 Brussels, Belgium. Univ Catholique Louvain, Dept Publ Hlth, Unit Ind Toxicol & Occupational Med, B-1200 Brussels, Belgium. Univ Catholique Louvain, Haemostasis & Thrombosis Unit, B-1200 Brussels, Belgium. Univ Catholique Louvain, Christian de Duve Inst Cellular Pathol, Cell Unit, B-1200 Brussels, Belgium. Univ Catholique Louvain, Dept Clin Chem, B-1200 Brussels, Belgium. Univ Catholique Louvain, Dept Pneumol Paediat, B-1200 Brussels, Belgium. Univ Hasselt, Ctr Milieukunde, Lab Cell Physiol, Diepenbeek, Belgium. Katholieke Univ Leuven, Ctr Human Genet, Louvain, Belgium. Erasmus Univ, Med Ctr, Dept Biochem, Rotterdam, Netherlands. Erasmus Univ, Med Ctr, Dept Cell Biol, Rotterdam, Netherlands.Devuyst, O, Univ Catholique Louvain, Div Nephrol, 10 Ave Hippocrate, B-1200 Brussels, Belgium.firstname.lastname@example.org|
|ISI #: ||000245873400010|
|Type: ||Journal Contribution|
|Validation: ||ecoom, 2008|
|Appears in Collections: ||Research publications|
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