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Cystic Fibrosis Is Associated with a Defect in Apical Receptor–Mediated Endocytosis in Mouse and Human Kidney

François Jouret^*, Alfred Bernard, Cédric Hermans, Geneviève Dom, Sara Terryn^||, Teresinha Leal^¶, Patrick Lebecque^**, Jean-Jacques Cassiman, Bob J. Scholte, Hugo R. de Jonge, Pierre J. Courtoy and Olivier Devuyst^*

^* Division of Nephrology, Department of Public Health, Unit of Industrial Toxicology and Occupational Medicine, Haemostasis and Thrombosis Unit, Christian de Duve Institute of Cellular Pathology, Cell Unit, ^¶ Department of Clinical Chemistry, and ^** Department of Pneumology–Paediatrics, Université catholique de Louvain, Brussels, ^|| Laboratory of Cell Physiology, Centrum voor Milieukunde, Universiteit Hasselt, Diepenbeek, and Center for Human Genetics, University of Leuven, Leuven, Belgium; and Departments of Biochemistry/Cell Biology, Erasmus University Medical Center, Rotterdam, The Netherlands

Address correspondence to: Dr. Olivier Devuyst, Division of Nephrology, Université catholique de Louvain, 10 Avenue Hippocrate, B-1200 Brussels, Belgium. Phone: +32-2-764-54-53; Fax: +32-2-764-54-55; E-mail: devuyst{at}nefr.ucl.ac.be

Received for publication March 24, 2006. Accepted for publication December 17, 2006.

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 ¹²⁵I-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^F/F 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.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673