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

  • Ion Channels, Receptors and Transporters
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Abstract

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.

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Acknowledgements

We thank Profs. R. Beauwens, J-J. Cassiman, and H. R. de Jonge for help and support in these studies, and Mrs. Y. Cnops of excellent technical assistance.

The study was supported by the Belgian agencies FNRS and FRSM (3.4.592.06F), the Foundation Alphonse and Jean Forton, a Concerted Research Action (10/15-029), an Inter-university Attraction Pole (IUAP P6/05), the Programme d’excellence Marshall DIANE (Région Wallone), the EUNEFRON (FP7, GA#201590) program of the European Community, and the National Centre of Competence in Research (NCCR) Kidney. CH is gratefully acknowledged.

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Authors and Affiliations

  1. Division of Nephrology, Université catholique de Louvain Medical School, Brussels, Belgium

    Claudia Raggi, François Jouret, Olivier Devuyst & Sara Terryn

  2. Louvain Center for Toxicology and Applied Pharmacology, Université catholique de Louvain Medical School, Brussels, Belgium

    Teresinha Leal

  3. Department of Applied Life Science, Sojo University, Kumamoto, Japan

    Kunio Fujiwara

  4. Institute of Physiology, Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland

    Olivier Devuyst

Authors
  1. Claudia Raggi
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  2. Kunio Fujiwara
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  3. Teresinha Leal
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  4. François Jouret
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  5. Olivier Devuyst
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  6. Sara Terryn
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Corresponding authors

Correspondence to Olivier Devuyst or Sara Terryn.

Additional information

Olivier Devuyst and Sara Terryn should be considered as joint senior/corresponding authors.

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Raggi, C., Fujiwara, K., Leal, T. et al. Decreased renal accumulation of aminoglycoside reflects defective receptor-mediated endocytosis in cystic fibrosis and Dent’s disease. Pflugers Arch - Eur J Physiol 462, 851–860 (2011). https://doi.org/10.1007/s00424-011-1026-2

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  • DOI: https://doi.org/10.1007/s00424-011-1026-2

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