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CFTR and defective endocytosis: new insights in the renal phenotype of cystic fibrosis

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Jouret, François [UCL] Devuyst, Olivier [UCL]

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 is associated with CF. Recent studies have shown that the level of CFTR mRNA in mouse kidney approaches that found in lung. CFTR is particularly abundant in the apical area of proximal tubule cells, where it co-distributes with the Cl(-)/H(+) exchanger ClC-5 and Rab5a in endosomes. The biological relevance of CFTR in proximal tubule endocytosis has been tested in CF mouse models and CF patients. Mice lacking CFTR show a defective receptor-mediated endocytosis, as evidenced by impaired uptake of (125)I-beta(2)-microglobulin, a decreased expression of the cubilin receptor in the kidney, and a significant excretion of cubilin and its low-molecular-weight ligands into the urine. Low-molecular-weight proteinuria (and particularly transferrinuria) is similarly detected in CF patients in comparison with normal controls or patients with chronic lung inflammation. These studies suggest that the functional loss of CFTR impairs the handling of low-molecular-weight proteins by the kidney, supporting a role of CFTR in receptor-mediated endocytosis in proximal tubule cells. The selective proteinuria should be integrated in the pathophysiology of multi-systemic complications increasingly observed in CF patients.

Document type Article de périodique (Journal article) – Article de recherche – Journal Article, Research Support, Non-U.S. Gov't, Review
Access type Accès restreint
Publication date 2009
Language Anglais
Journal information "Pflügers Archiv - European journal of physiology" - Vol. 457, no. 6, p. 1227-1236 (2009)
Peer reviewed yes
Publisher Springer ((Germany) Berlin)
issn 0031-6768
e-issn 1432-2013
Publication status Publié
Affiliations UCL - MD/MINT - Département de médecine interne
UCL - (SLuc) Service de néphrologie
MESH Subject Mice ; Kidney Tubules, Proximal - physiopathology ; Kidney - physiopathology ; Humans ; Endocytosis - physiology ; Cystic Fibrosis Transmembrane Conductance Regulator - genetics - physiology ; Cystic Fibrosis - physiopathology ; Chloride Channels - physiology ; Animals
Keywords Proximal tubule ; Kidney ; Chloride channel ; Cystic fibrosis transmembrane conductance regulator ; Protein metabolism
Links
  1. Barasch J, Kiss B, Prince A et al (1991) Defective acidification of intracellular organelles in cystic fibrosis. Nature 352:70–73
  2. Birn H, Christensen EI (2006) Renal albumin absorption in physiology and pathology. Kidney Int 69:440–449
  3. Bradbury NA (1999) Intracellular CFTR: localization and function. Physiol Rev 79:S175–S191
  4. Bradbury NA, Jilling T, Berta G et al (1992) Regulation of plasma membrane recycling by CFTR. Science 256:530–532
  5. Cheng SH, Gregory RJ, Marshall J et al (1990) Defective intracellular transport and processing of CFTR is the molecular basis of most cystic fibrosis. Cell 63:827–834
  6. Cheng J, Wang H, Guggino WB (2005) Regulation of cystic fibrosis transmembrane regulator trafficking and protein expression by a Rho family small GTPase TC10. J Biol Chem 280:3731–3739
  7. Christensen Erik Ilsø, Birn Henrik, Megalin and cubilin: multifunctional endocytic receptors, 10.1038/nrm778
  8. Christensen EI, Devuyst O, Dom G 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
  9. Christensen EI, Maunsbach AB (1979) Effects of dextran on lysosomal ultrastructure and protein digestion in renal proximal tubule. Kidney Int 16:301–311
  10. Conner SD, Schmid SL (2003) Regulated portals of entry into the cell. Nature 422:37–44
  11. Coudroy G, Gburek J, Kozyraki R et al (2005) Contribution of cubilin and amnionless to processing and membrane targeting of cubilin–amnionless complex. J Am Soc Nephrol 16:2330–2337
  12. Crawford I, Maloney PC, Zeitlin PL et al (1991) Immunocytochemical localization of the cystic fibrosis gene product CFTR. Proc Natl Acad Sci USA 88:9262–9266
  13. Denning GM, Anderson MP, Amara JF et al (1992) Processing of mutant cystic fibrosis transmembrane conductance regulator is temperature-sensitive. Nature 358:761–764
  14. Devuyst O, Beauwens R (1998) Ion transport and cystogenesis: the paradigm of autosomal dominant polycystic kidney disease. Adv Nephrol Necker Hosp 28:439–478
  15. Devuyst O, Burrow CR, Schwiebert EM et al (1996) Developmental regulation of CFTR expression during human nephrogenesis. Am J Physiol 271:F723–F735
  16. Devuyst O, Christie PT, Courtoy PJ 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
  17. Devuyst Olivier, Guggino William B., Chloride channels in the kidney: lessons learned from knockout animals, 10.1152/ajprenal.00184.2002
  18. Devuyst O, Pirson Y (2007) Genetics of hypercalciuric stone forming diseases. Kidney Int 72:1065–1072
  19. Dutzler R, Campbell EB, Cadene M, Chait BT, MacKinnon R (2002) X-ray structure of a ClC chloride channel at 3.0 A reveals the molecular basis of anion selectivity. Nature 415:287–294
  20. Egan ME, Glockner-Pagel J, Ambrose C et al (2002) Calcium-pump inhibitors induce functional surface expression of ΔF508-CFTR protein in cystic fibrosis epithelial cells. Nat Med 8:485–492
  21. Ellsworth RE, Jamison DC, Touchman JW et al (2000) Comparative genomic sequence analysis of the human and mouse cystic fibrosis transmembrane conductance regulator genes. Proc Natl Acad Sci USA 97:1172–1177
  22. Faundez V, Hartzell HC (2004) Intracellular chloride channels: determinants of function in the endosomal pathway. Sci STKE 233:re8
  23. French PJ, van Doorninck JH, Peters RH et al (1996) F508 mutation in mouse cystic fibrosis transmembrane conductance regulator results in a temperature-sensitive processing defect in vivo. J Clin Invest 98:1304–1312
  24. Fyfe JC, Madsen M, Højrup P et al (2003) The functional cobalamin (vitamin B12)-intrinsic factor receptor is a novel complex of cubilin and amnionless. Blood 103:1573–1579
  25. Gadsby DC, Vergani P, Csanady L (2006) The ABC protein turned chloride channel whose failure causes cystic fibrosis. Nature 440:477–483
  26. Gekle M (2005) Renal tubule albumin transport. Annu Rev Physiol 67:573–594
  27. Gibney EM, Goldfarb DS (2003) The association of nephrolithiasis with cystic fibrosis. Am J Kidney Dis 42:1–11
  28. Graves AR, Curran PK, Smith CL, Mindell JA (2008) The Cl−/H+ antiporter ClC-7 is the primary chloride permeation pathway in lysosomes. Nature 453:788–792
  29. Groman JD, Meyer ME, Wilmott RW et al (2002) Variant cystic fibrosis phenotypes in the absence of CFTR mutations. N Engl J Med 347:401–407
  30. Grubb BR, Boucher RC (1999) Pathophysiology of gene-targeted mouse models for cystic fibrosis. Physiol Rev 79:S193–S214
  31. Guggino WB (2004) The cystic fibrosis transmembrane regulator forms macromolecular complexes with PDZ domain scaffold proteins. Proc Am Thorac Soc 1:28–32
  32. Guggino WB, Stanton BA (2006) New insights into cystic fibrosis: molecular switches that regulate CFTR. Nat Rev Mol Cell Biol 7:426–436
  33. Günther W, Luchow A, Cluzeaud F et al (1998) ClC-5, the chloride channel mutated in Dent’s disease, colocalizes with the proton pump in endocytotically active kidney cells. Proc Natl Acad Sci USA 95:8075–8080
  34. Günther Willy, Piwon Nils, Jentsch Thomas J., The ClC-5 chloride channel knock-out mouse – an animal model for Dent's disease, 10.1007/s00424-002-0950-6
  35. Hanaoka K, Devuyst O, Schwiebert EM et al (1996) A role for CFTR in human autosomal dominant polycystic kidney disease. Am J Physiol 270:C389–C399
  36. Hara-Chikuma M, Wang Y, Guggino SE et al (2005) Impaired acidification in early endosomes of ClC-5 deficient proximal tubule. Biochem Biophys Res Commun 329:941–946
  37. Herak-Kramberger CM, Brown D, Sabolic I (1998) Cadmium inhibits vacuolar H+-ATPase and endocytosis in rat kidney cortex. Kidney Int 53:1713–1726
  38. Higgins CF (1992) ABC transporters: from microorganisms to man. Annu Rev Cell Biol 8:67–113
  39. Huber S, Braun G, Burger-Kentischer A et al (1998) CFTR mRNA and its truncated splice variant (TRN-CFTR) are differentially expressed during collecting duct ontogeny. FEBS Lett 423:362–366
  40. Hurtado-Lorenzo A, Skinner M, El Annan J et al (2006) V-ATPase interacts with ARNO and Arf6 in early endosomes and regulates the protein degradative pathway. Nat Cell Biol 8:124–136
  41. Jentsch TJ (2007) Chloride and the endosomal-lysosomal pathway: emerging roles of CLC chloride transporters. J Physiol 578:633–640
  42. Jentsch TJ, Maritzen T, Zdebik AA (2005) Chloride channel diseases resulting from impaired transepithelial transport or vesicular function. J Clin Invest 115:2039–2046
  43. Jouret F, Bernard A, Hermans C 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
  44. Kalantry S, Manning S, Haub O et al (2001) The amnionless gene, essential for mouse gastrulation, encodes a visceral-endoderm-specific protein with an extracellular cysteine-rich domain. Nat Genet 27:412–416
  45. Kalin N, Claass A, Sommer M et al (1999) ΔF508 CFTR protein expression in tissues from patients with cystic fibrosis. J Clin Invest 103:1379–1389
  46. Katz SM, Krueger LJ, Falkner B (1988) Microscopic nephrocalcinosis in cystic fibrosis. N Engl J Med 319:263–266
  47. Kennedy JD, Dinwiddie R, Daman-Willems C, Dillon MJ, Matthew DJ (1990) Pseudo-Bartter’s syndrome in cystic fibrosis. Arch Dis Child 65:786–787
  48. Kerem B, Rommens JM, Buchanan JA et al (1989) Identification of the cystic fibrosis gene: genetic analysis. Science 245:1073–1080
  49. Kibble JD, Balloch KJ, Neal AM et al (2001) Renal proximal tubule function is preserved in Cftrtm2cam ΔF508 cystic fibrosis mice. J Physiol 532:449–457
  50. Kibble JD, Neal AM, Colledge WH et al (2000) Evidence for cystic fibrosis transmembrane conductance regulator-dependent sodium reabsorption in kidney, using Cftrtm2cam mice. J Physiol 526:27–34
  51. Letz B, Korbmacher C (1997) cAMP stimulates CFTR-like Cl− channels and inhibits amiloride-sensitive Na+ channels in mouse CCD cells. Am J Physiol 272:C657–C666
  52. Li C, Naren AP (2005) Macromolecular complexes of cystic fibrosis transmembrane conductance regulator and its interacting partners. Pharmacol Ther 108:208–223
  53. Lloyd SE, Pearce SH, Fisher SE et al (1996) A common molecular basis for three inherited kidney stone diseases. Nature 379:445–449
  54. Lu M, Leng Q, Egan ME et al (2006) CFTR is required for PKA-regulated ATP sensitivity of Kir1.1 potassium channels in mouse kidney. J Clin Invest 116:797–807
  55. Lyon A, Bilton D (2002) Fertility issues in cystic fibrosis. Paediatr Respir Rev 3:236–240
  56. Magenheimer BS, St John PL, Isom KS et al (2006) Early embryonic renal tubules of wild-type and polycystic kidney disease kidneys respond to cAMP stimulation with cystic fibrosis transmembrane conductance regulator/Na(+),K(+),2Cl(−) Co-transporter-dependent cystic dilation. J Am Soc Nephrol 17:3424–3437
  57. Moestrup SK, Kozyraki R, Kristiansen M et al (1998) The intrinsic factor-vitamin B12 receptor and target of teratogenic antibodies is a megalin-binding peripheral membrane protein with homology to developmental proteins. J Biol Chem 273:5235–5242
  58. Morales MM, Carroll TP, Morita T et al (1996) Both the wild type and a functional isoform of CFTR are expressed in kidney. Am J Physiol 270:F1038–F1048
  59. MORALES MARCELO M., FALKENSTEIN DORIS, LOPES ANÍBAL GIL, The Cystic Fibrosis Transmembrane Regulator (CFTR) in the kidney, 10.1590/s0001-37652000000300013
  60. Moriyama Y, Nelson N (1987) The purified ATPase from chromaffin granule membranes is an anion-dependent proton pump. J Biol Chem 262:9175–9180
  61. Nielsen R, Courtoy PJ, Jacobsen C et al (2007) Endocytosis provides a major alternative pathway for lysosomal biogenesis in kidney proximal tubular cells. Proc Natl Acad Sci USA 104:5407–5412
  62. O’Connor TM, McGrath DS, Short C et al (2002) Subclinical anemia of chronic disease in adult patients with cystic fibrosis. J Cyst Fibros 1:31–34
  63. Ostedgaard LS, Rogers CS, Dong Q et al (2007) Processing and function of CFTR-DeltaF508 are species-dependent. Proc Natl Acad Sci USA 104:15370–15375
  64. Pasyk EA, Foskett JK (1995) Mutant (delta F508) cystic fibrosis transmembrane conductance regulator Cl− channel is functional when retained in endoplasmic reticulum of mammalian cells. J Biol Chem 270:12347–12350
  65. Persu A, Devuyst O, Lannoy N 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
  66. Picollo A, Pusch M (2005) Chloride/proton antiporter activity of mammalian CLC proteins ClC-4 and ClC-5. Nature 436:420–423
  67. Piwon N, Günther W, Schwake M et al (2000) ClC-5 Cl–channel disruption impairs endocytosis in a mouse model for Dent’s disease. Nature 408:369–373
  68. Pond MN, Morton AM, Conway SP (1996) Functional iron deficiency in adults with cystic fibrosis. Respir Med 90:409–413
  69. Poschet JF, Fazio JA, Timmins GS et al (2006) Endosomal hyperacidification in cystic fibrosis is due to defective nitric oxide-cylic GMP signalling cascade. EMBO Rep 7:553–559
  70. Poschet JF, Skidmore J, Boucher JC et al (2002) Hyperacidification of cellubrevin endocytic compartments and defective endosomal recycling in cystic fibrosis respiratory epithelial cells. J Biol Chem 277:13959–13965
  71. Riordan JR, Rommens JM, Kerem B et al (1989) Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 245:1066–1073
  72. Rogers CS, Hao Y, Rokhlina T et al (2008) Production of CFTR-null and CFTR-DeltaF508 heterozygous pigs by adeno-associated virus-mediated gene targeting and somatic cell nuclear transfer. J Clin Invest 118:1571–1577
  73. Rowe SM, Miller S, Sorscher EJ (2005) Cystic fibrosis. N Engl J Med 352:1992–2001
  74. Rowntree RK, Harris A (2003) The phenotypic consequences of CFTR mutations. Ann Hum Genet 67:471–485
  75. Samaniego-Picota MD, Whelton A (1996) Aminoglycoside-induced nephrotoxicity in cystic fibrosis: a case presentation and review of the literature. Am J Ther 3:248–257
  76. Scheel O, Zdebik AA, Lourdel S et al (2005) Voltage-dependent electrogenic chloride/proton exchange by endosomal CLC proteins. Nature 436:424–427
  77. Scheinman SJ (1998) X-linked hypercalciuric nephrolithiasis: clinical syndromes and chloride channel mutations. Kidney Int 53:3–17
  78. Schmitz C, Hilpert J, Jacobsen C et al (2002) Megalin deficiency offers protection from renal aminoglycoside accumulation. J Biol Chem 277:618–622
  79. Sheppard DN, Welsh MJ (1999) Structure and function of the CFTR chloride channel. Physiol Rev 79:S23–S45
  80. Shi LB, Fushimi K, Bae HR et al (1991) Heterogeneity in ATP-dependent acidification in endocytic vesicles from kidney proximal tubule. Measurement of pH in individual endocytic vesicles in a cell-free system. Biophys J 59:1208–1217
  81. Sojo A, Rodriguez-Soriano J, Vitoria JC, Vazquez C, Ariceta G, Villate A (1994) Chloride deficiency as a presentation or complication of cystic fibrosis. Eur J Pediatr 153:825–828
  82. van Doorninck JH, French PJ, Verbeek E et al (1995) A mouse model for the cystic fibrosis ΔF508 mutation. EMBO J 14:4403–4411
  83. Veeze HJ, Halley DJ, Bijman J et al (1994) Determinants of mild clinical symptoms in cystic fibrosis patients. Residual chloride secretion measured in rectal biopsies in relation to the genotype. J Clin Invest 93:461–466
  84. Wagner CA, Finberg KE, Breton S, Marshansky V, Brown D, Geibel JP (2004) Renal vacuolar H+-ATPase. Physiol Rev 84:1263–1314
  85. Wang SS, Devuyst O, Courtoy PJ et al (2000) Mice lacking renal chloride channel, CLC-5, are a model for Dent’s disease, a nephrolithiasis disorder associated with defective receptor-mediated endocytosis. Hum Mol Genet 9:2937–2945
  86. Wang Y, Cai H, Cebotaru L et al (2005) ClC-5: role in endocytosis in the proximal tubule. Am J Physiol Renal Physiol 289:F850–F862
  87. Ward CL, Omura S, Kopito RR (1995) Degradation of CFTR by the ubiquitin–proteasome pathway. Cell 83:121–127
  88. Yang B, Sonawane ND, Zhao D et al (2008) Small-molecule CFTR inhibitors slow cyst growth in polycystic kidney disease. J Am Soc Nephrol 19:1300–1310
Bibliographic reference Jouret, François ; Devuyst, Olivier. CFTR and defective endocytosis: new insights in the renal phenotype of cystic fibrosis. In: Pflügers Archiv - European journal of physiology, Vol. 457, no. 6, p. 1227-1236 (2009)
Permanent URL http://hdl.handle.net/2078.1/19628