Decreased renal accumulation of aminoglycoside reflects defective receptor-mediated endocytosis in cystic fibrosis and Dent’s disease

• Published in: Pflügers Archiv Vol. 462; no. 6; pp. 851 - 860
• Main Authors: Raggi, Claudia, Fujiwara, Kunio, Leal, Teresinha, Jouret, François, Devuyst, Olivier, Terryn, Sara
• Format: Journal Article Web Resource
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.12.2011; Springer Nature B.V; Springer
• Subjects: Albumin; Aminoglycosides - metabolism; Animals; Anti-Bacterial Agents - metabolism; Biomedical and Life Sciences; Biomedicine; Cell Biology; Cells, Cultured; Chloride Channels - genetics; Chloride Channels - metabolism; Chloride Channels/genetics/metabolism; Cystic Fibrosis - physiopathology; Cystic Fibrosis Transmembrane Conductance Regulator - genetics; Cystic Fibrosis Transmembrane Conductance Regulator - metabolism; Cystic Fibrosis Transmembrane Conductance Regulator/genetics/metabolism; Dent Disease - physiopathology; Endocytosis - physiology; Gentamicins - metabolism; Human health sciences; Human Physiology; Humans; Ion Channels; Kidney - metabolism; Kidney Tubules, Proximal - cytology; Kidney Tubules, Proximal - metabolism; Kidney Tubules, Proximal/cytology/metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Medicine; Neurosciences; Receptors; Receptors and Transporters; Sciences de la santé humaine; Urologie & néphrologie; Urology & nephrology; Chloride channel; Proximal tubule; Epithelial transport; Endocytosis; Kidney
• ISSN: 0031-6768; 1432-2013; 1432-2013
• DOI: 10.1007/s00424-011-1026-2

The clinical use of aminoglycoside (AG) antibiotics is limited by their renal toxicity, which is caused by drug accumulation in proximal tubule (PT) cells. Clinical studies reported that renal clearance of AG is enhanced in cystic fibrosis (CF) patients, which might reflect the role of CFTR in PT cell endocytosis. In order to assess the role of chloride transporters on the renal handling of AG, we investigated gentamicin uptake and renal accumulation in mice lacking functional CFTR ( Cftr ∆F/∆ F ) or knock-out for the Cl − /H + exchanger ClC-5 ( Clcn5 Y/− ). The latter represent a paradigm of PT dysfunction and defective receptor-mediated endocytosis. As compared with controls, Cftr ∆F/∆ F and Clcn5 Y / − mice showed a 15% to 85% decrease in gentamicin accumulation in the kidney, respectively, in absence of renal failure. Studies on primary cultures of Cftr ∆F/∆ F and Clcn5 Y/− mouse PT cells confirmed the reduction in gentamicin uptake, although colocalization with endosomes and lysosomes was maintained. Quantification of endocytosis in PT cells revealed that gentamicin, similar to albumin, preferentially binds to megalin. The functional loss of ClC-5 or CFTR was reflected by a decrease of the endocytic uptake of gentamicin, with a more pronounced effect in cells lacking ClC-5. These results support the concept that CFTR, as well as ClC-5, plays a relevant role in PT cell endocytosis. They also demonstrate that the functional loss of these two chloride transporters is associated with impaired uptake of AG in PT cells, reflected by a decreased renal accumulation of the drug.