[en] 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.
Disciplines :
Urology & nephrology
Author, co-author :
Raggi, Claudia
Fujiwara, Kunio
Leal, Teresinha
JOURET, François ; Centre Hospitalier Universitaire de Liège - CHU > Néphrologie
Devuyst, Olivier
Terryn, Sara
Language :
English
Title :
Decreased renal accumulation of aminoglycoside reflects defective receptor-mediated endocytosis in cystic fibrosis and Dent's disease.
GB Appel 1990 Aminoglycoside nephrotoxicity Am J Med 88 165 209 10.1016/0002-9343(90)90082-O
D Bockenhauer MJ Hug R Kleta 2009 Cystic fibrosis, aminoglycoside treatment and acute renal failure: the not so gentle micin Pediatr Nephrol 24 925 928 19005685 10.1007/s00467-008-1036-2
SH Cheng RJ Gregory J Marshall, et al. 1990 Defective intracellular transport and processing of CFTR is the molecular basis of most cystic fibrosis Cell 63 827 834 1699669 10.1016/0092-8674(90)90148-8 1:CAS:528: DyaK3MXnvFKguw%3D%3D (Pubitemid 120035055)
EI Christensen H Birn 2002 Megalin and cubilin: multifunctional endocytic receptors Nat Rev Mol Cell Biol 3 256 266 11994745 1:CAS:528: DC%2BD38XjslOnur4%3D (Pubitemid 34619261)
EI Christensen O Devuyst G Dom, et al. 2003 Loss of chloride channel ClC-5 impairs endocytosis by defective trafficking of megalin and cubilin in kidney proximal tubules Proc Natl Acad Sci USA 100 8472 8477 12815097 10.1073/pnas.1432873100 1:CAS:528:DC%2BD3sXlsFGntbg%3D (Pubitemid 36842569)
EI Christensen PJ Verroust R Nielsen 2009 Receptor-mediated endocytosis in renal proximal tubule Pflugers Arch 458 1039 1048 19499243 10.1007/s00424-009-0685-8 1:CAS:528:DC%2BD1MXhtFensbbJ
O Devuyst PT Christie PJ Courtoy, et al. 1999 Intra-renal and subcellular distribution of the human chloride channel, CLC-5, reveals a pathophysiological basis for Dent's disease Hum Mol Genet 8 247 257 9931332 10.1093/hmg/8.2.247 1:CAS:528:DyaK1MXht12itrY%3D (Pubitemid 29054266)
K Fujiwara M Shin H Matsunaga, et al. 2009 Light-microscopy immunocytochemistry for gentamicin and its use for studying uptake of the drug in kidney Antimicrob Agents Chemother 53 3302 3307 19451299 10.1128/AAC.01627-08 1:CAS:528:DC%2BD1MXps1yhur0%3D
F Jouret A Bernard C Hermans, et al. 2007 Cystic fibrosis is associated with a defect in apical receptor-mediated endocytosis in mouse and human kidney J Am Soc Nephrol 18 707 718 17287432 10.1681/ASN.2006030269 1:CAS:528: DC%2BD2sXjs1Grsrg%3D (Pubitemid 46434488)
F Jouret O Devuyst 2009 CFTR and detective endocytosis: new insights in the renal phenotype of cystic fibrosis Pflugers Arch 457 1227 1236 18839205 10.1007/s00424-008-0594-2 1:CAS:528:DC%2BD1MXivFynurg%3D
WJ Jusko LL Mosovich LM Gerbracht ME Mattar SJ Yaffe 1975 Enhanced renal excretion of dicloxacillin in patients with cystic fibrosis Pediatrics 56 1038 1044 1196754 1:CAS:528:DyaE28Xotl2ltw%3D%3D
JM Lopez-Novoa Y Quiros L Vicente AI Morales FJ Lopez-Hernandez 2011 New insights into the mechanism of aminoglycoside nephrotoxicity: an integrative point of view Kidney Int 79 33 45 20861826 10.1038/ki.2010.337 1:CAS:528:DC%2BC3cXhsFGrur7F
SK Moestrup S Cui H Vorum, et al. 1995 Evidence that epithelial glycoprotein 330/megalin mediates uptake of polybasic drugs J Clin Investig 96 1404 1413 7544804 10.1172/JCI118176 1:CAS:528:DyaK2MXnvVGqtLg%3D
J Nagai M Takano 2004 Molecular aspects of renal handling of aminoglycosides and strategies for preventing the nephrotoxicity Drug Metab Pharmacokin 19 159 170 10.2133/dmpk.19.159 1:CAS:528:DC%2BD2cXmvFKqs78%3D
J Nagai H Tanaka N Nakanishi, et al. 2001 Role of megalin in renal handling of aminoglycosides Am J Physiol Ren Physiol 281 F337 F344 1:CAS:528:DC%2BD3MXmtVCksrk%3D
TD Nolin J Himmelfarb 2010 Mechanisms of drug induced nephrotoxicity Handb Exp Pharmacol 196 111 130 20020261 10.1007/978-3-642-00663-0-5 1:CAS:528:DC%2BC3cXnvVynu70%3D
A Persu O Devuyst N Lannoy, et al. 2000 CF gene and cystic fibrosis transmembrane conductance regulator expression in autosomal dominant polycystic kidney disease J Am Soc Nephrol 11 2285 2296 11095651 1:CAS:528: DC%2BD3cXptVagsLY%3D
N Piwon W Günther M Schwake MR Bösl TJ Jentsch 2000 ClC-5 Cl- channel disruption impairs endocytosis in a mouse model for Dent's disease Nature 408 369 373 11099045 10.1038/35042597 1:CAS:528: DC%2BD3cXosVertLY%3D
AA Reed NY Loh S Terryn, et al. 2010 CLC-5 and KIF3B interact to facilitate CLC-5 plasma membrane expression, endocytosis, and microtubular transport: relevance to pathophysiology of Dent's disease Am J Physiol 298 F365 F380 10.1152/ajprenal.00038.2009 1:CAS:528:DC%2BC3cXhvVykt78%3D
SM Rowe S Miller EJ Sorscher 2005 Cystic fibrosis New Eng J Med 352 1992 2001 15888700 10.1056/NEJMra043184 1:CAS:528:DC%2BD2MXjvFyrtLY%3D (Pubitemid 40638370)
C Schmitz J Hilpert C Jacobsen, et al. 2002 Megalin deficiency offers protection from renal aminoglycoside accumulation J Biol Chem 277 618 622 11700326 10.1074/jbc.M109959200 1:CAS:528:DC%2BD38XjslGmsA%3D%3D (Pubitemid 34952099)
H Servais A Ortiz O Devuyst S Denamur PM Tulkens MP Mingeot-Leclercq 2008 Renal cell apoptosis induced by nephrotoxic drugs: cellular and molecular mechanisms and potential approaches to modulation Apoptosis 13 11 32 17968659 10.1007/s10495-007-0151-z 1:CAS:528:DC%2BD1cXjt12hurk%3D
N Soulsby H Greville K Coulthard, et al. 2009 Renal dysfunction in cystic fibrosis: is there cause of concern? Pediatr Pulmonol 44 947 953 19728391 10.1002/ppul.21086
M Susanto LZ Benet 2002 Can the enhanced renal clearance of antibiotics in cystic fibrosis patients be explained by P-glycoprotein transport? Pharm Res 19 457 462 12033380 10.1023/A:1015191511817 1:CAS:528:DC%2BD38XjvFejs7w%3D (Pubitemid 34408945)
K Tanaka S Terryn L Geffers S Garbay M Pontoglio O Devuyst 2010 The transcription factor HNF1α regulates expression of chloride-proton exchanger ClC-5 in the renal proximal tubule Am J Physiol Ren Physiol 299 F1339 F1347 10.1152/ajprenal.00077.2010 1:CAS:528:DC%2BC3cXhs1elsLfL
J Tauris EI Christensen A Nykjaer, et al. 2009 Cubilin and megalin co-localize in the neonatal inner ear Audiol Neurootol 14 267 278 19202329 10.1159/000199446 1:CAS:528:DC%2BD1MXmtlertb0%3D
S Terryn F Jouret F Vandenabeele, et al. 2007 A primary culture of mouse proximal tubular cells, established on collagen-coated membranes Am J Physiol 293 F476 F485 10.1152/ajprenal.00363.2006 1:CAS:528:DC%2BD2sXptlyqtLk%3D (Pubitemid 47358117)
DJ Touw 1998 Clinical pharmacokinetics of antimicrobial drugs in cystic fibrosis Pharm World Sci 20 149 160 9762727 10.1023/A:1008634911114 1:CAS:528:DyaK1MXltVyltg%3D%3D (Pubitemid 28393870)
JH Van Doorninck PJ French E Verbeek, et al. 1995 A mouse model of cystic fibrosis transmembrane conductance regulator results in a temperature-sensitive processing defect in vivo EMBO J 14 4403 4411 7556083
SS Wang O Devuyst PJ Courtoy, et al. 2000 Mice lacking renal chloride channel, ClC-5, are a model for Dent's disease, a nephrolithiasis disorder associated with a defective receptor-mediated endocytosis Hum Mol Genet 9 2937 2945 11115837 10.1093/hmg/9.20.2937 1:CAS:528:DC%2BD3MXjt1Sr (Pubitemid 32000767)
R Zietse R Zoutendijk EJ Hoorn 2009 Fluid, electrolyte and acid-base disorders associated with antibiotic therapy Nat Rev Nephrol 5 193 202 19322184 10.1038/nrneph.2009.17 1:CAS:528:DC%2BD1MXjs1ynsbc%3D