The epithelial sodium channel: from molecule to disease

Part of the Reviews of Physiology, Biochemistry and Pharmacology book series (REVIEWS, volume 151)


Genetic analysis has demonstrated that Na absorption in the aldosterone-sensitive distal nephron (ASDN) critically determines extracellular blood volume and blood pressure variations. The epithelial sodium channel (ENaC) represents the main transport pathway for Na+ absorption in the ASDN, in particular in the connecting tubule (CNT), which shows the highest capacity for ENaC-mediated Na+ absorption. Gain-of-function mutations of ENaC causing hypertension target an intracellular proline-rich sequence involved in the control of ENaC activity at the cell surface. In animal models, these ENaC mutations exacerbate Na+ transport in response to aldosterone, an effect that likely plays an important role in the development of volume expansion and hypertension. Recent studies of the functional consequences of mutations in genes controlling Na+ absorption in the ASDN provide a new understanding of the molecular and cellular mechanisms underlying the pathogenesis of salt-sensitive hypertension.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Abriel H, Loffing J, Rebhun JF, Pratt JH, Schild L, Horisberger JD, Rotin D, Staub O (1999) Defective regulation of the ENaC by Nedd4 in Liddle’s syndrome. J Clin Invest 103:667–673PubMedGoogle Scholar
  2. Almeida AJ, Burg MB (1982) Sodium transport in the rabbit connecting tubule. Am JPhysiol 243:F330–F334Google Scholar
  3. Alvarez de la Rosa D, Zhang P, Naray-Fejes-Toth A, Fejes-Toth G, Canessa CM (1999) The serum and glucocorticoid kinase sgk increases the abundance of epithelial sodium channels in the plasma membrane of Xenopus oocytes. J Biol Chem 274:37834–37839PubMedCrossRefGoogle Scholar
  4. Auberson M, Hoffmann-Pochon N, Vandewalle A, Kellenberger S, Schild L (2003) ENaC mutants causing Liddle’s syndrome retain ability to respond to aldosterone and vasopressin. Am J Physiol Renal Physiol 285:F459–F471PubMedGoogle Scholar
  5. Barker PM, Nguyen MS, Gatzy JT, Grubb B, Norman H, Hummler E, Rossier B, Boucher RC, Koller B (1998) Role of γ-ENaC subunit in lung liquid clearance and electrolyte balance in newborn mice. J Clin Invest 102: 1634–1640PubMedGoogle Scholar
  6. Bonny O, Rossier BC (2002) Disturbances of Na/K balance: pseudohypoaldosteronism revisited. J Am Soc Nephrol 13:2399–2414PubMedCrossRefGoogle Scholar
  7. Boucher RC (2004) New concepts of the pathogenesis of cystic fibrosis lung disease. Eur Respir J 23: 146–158PubMedCrossRefGoogle Scholar
  8. Burch LH, Talbot CR, Knowles MR, Canessa CM, Rossier BC, Boucher RC (1995) Relative expression of the human ENaC subunits in normal and cystic fibrosis airways. Am J Physiol 269:C511–C518PubMedGoogle Scholar
  9. Canessa CM, Horisberger JD, Rossier BC (1993) Epithelial sodium channel related to proteins involved in neurodegeneration. Nature 361:467–470PubMedCrossRefGoogle Scholar
  10. Canessa CM, Schild L, Buell G, Thorens B, Gautschi I, Horisberger JD, Rossier BC (1994) Amiloride-sensitive ENaC is made of three homologous subunits. Nature 367:463–467PubMedCrossRefGoogle Scholar
  11. Chang SS, Gründer S, Hanukoglu A, Rösler A, Mathew PM, Hanukoglu I, Schild L, Lu Y, Shimkets RA, Nelson-Williams C, Rossier BC, Lifton RP (1996) Mutations in subunits of the epithelial sodium channel cause salt wasting with hyperkalaemic acidosis, pseudohypoaldosteronism type 1. Nat Genet 12:248–253PubMedCrossRefGoogle Scholar
  12. Chen SY, Bhargava A, Mastroberardino L, Meijer OC, Wang J, Buse P, Firestone GL, Verrey F, Pearce D (1999) Epithelial sodium channel regulated by aldosterone-induced protein sgk. Proc Natl Acad Sci 96:2514–2519PubMedCrossRefGoogle Scholar
  13. Coscoy S, Lingueglia E, Lazdunski M, Barbry P (1998) The phe-met-arg-phe-amide-activated sodium channel is a tetramer. J Biol Chem 273:8317–8322PubMedCrossRefGoogle Scholar
  14. Costanzo LS (1984) Comparison of calcium and sodium transport in early and late rat distal tubules: effect of amiloride. Am J Physiol 246:F937–F945PubMedGoogle Scholar
  15. Dahlmann A, Pradervand SP, Hummler E, Rossier BC, Frindt G, Palmer LG (2003) Mineralocorticoid regulation of ENaC is maintained in a mouse model of Liddle’s syndrome. Am J Physiol Renal Physiol 285:F310–F318PubMedGoogle Scholar
  16. Debonneville C, Flores SY, Kamynina E, Plant PJ, Tauxe C, Thomas MA, Munster C, Chraibi A, Pratt JH, Horisberger JD, Pearce D, Loffing J, Staub O (2001) Phosphorylation of Nedd4-2 by Sgk1 regulates ENaC cell surface expression. EMBO J 20:7052–7059PubMedCrossRefGoogle Scholar
  17. Dijkink L, Hartog A, Van Os CH, Bindels RJM (2002) The epithelial sodium channel ENaC is intracellularly located as a tetramer. Pflugers Arch-Eur J Physiol 444:549–555CrossRefGoogle Scholar
  18. Dinudom A, Young JA, Cook DI (1993) Amiloride-sensitive Na+ current in the granular duct cells of mouse mandibular glands. Pflugers Arch. 423:164–166PubMedCrossRefGoogle Scholar
  19. Driscoll M, Chalfie M (1991) The mec-4 gene is a member of a family of Caenorhabditis elegans genes that can mutate to induce neuronal degeneration. Nature 349:588–593PubMedCrossRefGoogle Scholar
  20. Duc C, Farman N, Canessa CM, Bonvalet JP, Rossier BC (1994) Cell-specific expression of epithelial sodium channel α, β, and γ subunits in aldosterone-responsive epithelia from the rat: Localization by in situ hybridization and immunocytochemistry. J Cell Biol 127:1907–1921PubMedCrossRefGoogle Scholar
  21. Epple HJ, Amasheh S, Mankertz J, Goltz M, Schulzke JD, Fromm M (2000) Early aldosterone effect in distal colon by transcriptional regulation of ENaC subunits. Am J Physiol Gastrointest Liver Physiol 278:G718–G724PubMedGoogle Scholar
  22. Farman N, Talbot CR, Boucher R, Fay M, Canessa C, Rossier B, Bonvalet JP (1997) Noncoordinated expression of α, β, and γ subunit mRNAs of epithelial Na+ channel along rat respiratory tract. Am J Physiol Cell Physiol 272:C131–C141Google Scholar
  23. Firsov D, Schild L, Gautschi I, Mérillat AM, Schneeberger E, Rossier BC (1996) Cell surface expression of the epithelial Na channel and a mutant causing Liddle syndrome: A quantitative approach. Proc Natl Acad Sci 93: 15370–15375PubMedCrossRefGoogle Scholar
  24. Firsov D, Gautschi I, Merillat AM, Rossier BC, Schild L (1998) The heterotetrameric architecture of the epithelial sodium channel ENaC. EMBO J 17:344–352PubMedCrossRefGoogle Scholar
  25. Firsov D, Robert-Nicoud M, Gruender S, Schild L, Rossier BC (1999) Mutational analysis of cysteine-rich domains of the epithelium sodium channel ENaC—identification of cysteines essential for channel expression at the cell surface. J Biol Chem 274:2743–2749PubMedCrossRefGoogle Scholar
  26. Frindt G, Palmer LG (2003) Na channels in the rat connecting tubule. Am J Physiol Renal PhysiolGoogle Scholar
  27. Frindt G, Masilamani S, Knepper MA, Palmer LG (2001) Activation of epithelial Na channels during shortterm Na deprivation. Am J Physiol 280:F112–F118Google Scholar
  28. Frindt G, McNair T, Dahlmann A, Jacobs-Palme E, Palmer LG (2002) Epithelial Na channels and short-term renal response to salt deprivation. Am J Physiol Renal Physiol 283:F717–F726PubMedGoogle Scholar
  29. Geller DS, Rodriguezsoriano J, Boado AV, Schifter S, Bayer M, Chang SS, Lifton RP (1998) Mutations in the mineralocorticoid receptor gene cause autosomal dominant pseudohypoaldosteronism type 1. Nat Genet 19: 279–281PubMedCrossRefGoogle Scholar
  30. Geller DS, Farhi A, Pinkerton N, Fradley M, Moritz M, Spitzer A, Meinke G, Tsai FTF, Sigler PB, Lifton RP (2000) Activating mineralocorticoid receptor mutation in hypertension exacerbated by pregnancy. Science 289: 119–123PubMedCrossRefGoogle Scholar
  31. Grantham JJ, Burg MB, Orloff J (1970) The nature of transtubular sodium and potassium transport in isolated rabbit renal cortical collecting tubules. J Clin Invest 49:1815–1826PubMedCrossRefGoogle Scholar
  32. Grunder S, Firsov D, Chang SS, Jaeger NF, Gautschi I, Schild L, Lifton RP, Rossier BC (1997) A mutation causing pseudohypoaldosteronism type 1 identifies a conserved glycine that is involved in the gating of the epithelial sodium channel. EMBO J 16:899–907PubMedCrossRefGoogle Scholar
  33. Guyton AC (1992) Kidneys and fluids in pressure regulation. Small volume but large pressure changes. Hypertension 19:12–18Google Scholar
  34. Hager H, Kwon TH, Vinnikova AK, Masilamani S, Brooks HL, Frokiaer J, Knepper MA, Nielsen S (2001) Immunocytochemical and immunoelectron microscopic localization of α-, β-, and γ-ENaC in rat kidney. Am J Physiol Renal Physiol 280:F1093–F1106PubMedGoogle Scholar
  35. Hanukoglu A (1991) Type I pseudohypoaldosteronism includes two clinically and genetically distinct entities with either renal or multiple target organ defects. J Clin Endocrinol Metab 73:936–944PubMedCrossRefGoogle Scholar
  36. Hanwell D, Ishikawa T, Saleki R, Rotin D (2002) Trafficking and cell surface stability of the epithelial Na+ channel expressed in epithelial Madin-Darby canine kidney cells. J Biol Chem 277:9772–9779PubMedCrossRefGoogle Scholar
  37. Hawk CT, Li L, Schafer JA (1996) AVP and aldosterone at physiological concentrations have synergistic effects on Na+ transport in rat CCD. Kidney Int Suppl 57:S35–41PubMedGoogle Scholar
  38. Henry PC, Kanelis V, O’Brien MC, Kim B, Gautschi I, Forman-Kay J, Schild L, Rotin D (2003) Affinity and specificity of interactions between Nedd4 isoforms and the epithelial Na+ channel. J Biol Chem 278: 20019–20028PubMedCrossRefGoogle Scholar
  39. Hiltunen TP, Hannila-Handelberg T, Petajaniemi N, Kantola I, Tikkanen I, Virtamo J, Gautschi I, Schild L, Kontula K (2002) Liddle’s syndrome associated with a point mutation in the extracellular domain of the epithelial sodium channel gamma subunit. J Hypertens 20:2383–2390PubMedCrossRefGoogle Scholar
  40. Hummler E, Barker P, Gatzy J, Beermann F, Verdumo C, Schmidt A, Boucher RC, Rossier BC (1996) Early death due to defective neonatal lung liquid clearance in a ENaC-deficient mice. Nat Genet 12:325–328PubMedCrossRefGoogle Scholar
  41. Kamynina E, Debonneville C, Bens M, Vandewalle A, Staub O (2001a) A novel mouse Nedd4 protein suppresses the activity of the epithelial Na+ channel. FASEB J 15:204–214PubMedCrossRefGoogle Scholar
  42. Kamynina E, Tauxe C, Staub O (2001b) Distinct characteristics of two human Nedd4 proteins with respect to epithelial Na+ channel regulation. Am J Physiol Renal Physiol 281:F469–F477PubMedGoogle Scholar
  43. Kanelis V, Rotin D, Forman-Kay JD (2001) Solution structure of a Nedd4 WW domain-ENaC peptide complex. Nat Struct Biol 8:407–412PubMedCrossRefGoogle Scholar
  44. Kellenberger S, Schild L (2002) Epithelial sodium channel/degenerin family of ion channels: a variety of functions for a shared structure. Physiol Rev 82:735–767PubMedGoogle Scholar
  45. Kellenberger S, Gautschi I, Schild L (1999a) A single point mutation in the pore region of the epithelial Na+ channel changes ion selectivity by modifying molecular sieving. Proc Natl Acad Sci 96:4170–4175PubMedCrossRefGoogle Scholar
  46. Kellenberger S, Hoffmann-Pochon N, Gautschi I, Schneeberger E, Schild L (1999b) On the molecular basis of ion permeation in the epithelial Na+ channel. J Gen Physiol 114:13–30PubMedCrossRefGoogle Scholar
  47. Kellenberger S, Gautschi I, Schild L (2002) An external site controls closing of the epithelial Na+ channel ENaC. J Physiol London 543:413–424PubMedCrossRefGoogle Scholar
  48. Koefoed-Johnson V, Ussing HH (1958) The nature of frog skin potential. Acta Physiol Scand 42:298–308CrossRefGoogle Scholar
  49. Kosari F, Sheng SH, Li JQ, Mak DD, Foskett JK, Kleyman TR (1998) Subunit stoichiometry of the epithelial sodium channel. J Biol Chem 273:13469–13474PubMedCrossRefGoogle Scholar
  50. Liddle GW, Bledsoe T, Coppage WS (1963) A familial renal disorder simulating primary aldosteronism but with negligible aldosterone secretion. Trans Assoc Am Physicians 76:199–213Google Scholar
  51. Lifton RP (1996) Molecular genetics of human blood pressure variation. Science 272:676–680PubMedCrossRefGoogle Scholar
  52. Lifton RP, Gharavi AG, Geller DS (2001) Molecular mechanisms of human hypertension (review). Cell 104: 545–556PubMedCrossRefGoogle Scholar
  53. Lindemann B (1996) Taste reception. Physiol Rev 76:718–766PubMedGoogle Scholar
  54. Lingueglia E, Voilley N, Waldmann R, Lazdunski M, Barbry P (1993) Expression cloning of an epithelial amiloride-sensitive Na+ channel. FEBS Lett 318:95–99PubMedCrossRefGoogle Scholar
  55. Loffing J, Kaissling B (2003) Sodium and calcium transport pathways along the mammalian distal nephron: from rabbit to human. Am J Physiol Renal Physiol 284:F628–F643PubMedGoogle Scholar
  56. Loffing J, Loffing-Cueni D, Macher A, Hebert SC, Olson B, Knepper MA, Rossier BC, Kaissling B (2000a) Localization of epithelial sodium channel and aquaporin-2 in rabbit kidney cortex. Am J Physiol Renal Physiol 278:F530–F539PubMedGoogle Scholar
  57. Loffing J, Pietri L, Aregger F, Bloch-Faure M, Ziegler U, Meneton P, Rossier BC, Kaissling B (2000b) Differential subcellular localization of ENaC subunits in mouse kidney in response to high-and low-Na diets. Am J Physiol Renal Physiol 279:F252–F258PubMedGoogle Scholar
  58. Loffing J, Loffing-Cueni D, Valderrabano V, Klausli L, Hebert SC, Rossier BC, Hoenderop JGJ, Bindels RJM, Kaissling B (2001a) Distribution of transcellular calcium and sodium transport pathways along mouse distal nephron. Am J Physiol Renal Physiol 281:F1021–F1027PubMedGoogle Scholar
  59. Loffing J, Zecevic M, Feraille E, Kaissling B, Asher C, Rossier BC, Firestone GL, Pearce D, Verrey F (2001b) Aldosterone induces rapid apical translocation of ENaC in early portion of renal collecting system: possible role of SGK. Am J Physiol Renal Physiol 280:F675–F682PubMedGoogle Scholar
  60. May A, Puoti A, Gaeggeler HP, Horisberger JD, Rossier BC (1997) Early effect of aldosterone on the rate of synthesis of the epithelial sodium channel a subunit in A6 renal cells. J Am Soc Nephrol 8:1813–1822PubMedGoogle Scholar
  61. McDonald FJ, Yang BL, Hrstka RF, Drummond HA, Tarr DE, McCray PB, Stokes JB, Welsh MJ, Williamson RA (1999) Disruption of the β subunit of the epithelial Na+ channel in mice: hyperkalemia and neonatal death associated with a pseudohypoaldosteronism phenotype. Proc Natl Acad Sci 96:1727–1731PubMedCrossRefGoogle Scholar
  62. Morris RG, Schafer JA (2002) cAMP increases density of ENaC subunits in the apical membrane of MDCK cells in direct proportion to amiloride-sensitive Na+ transport. J Gen Physiol 120:71–85PubMedCrossRefGoogle Scholar
  63. Naray FT, Canessa C, Cleaveland ES, Aldrich G, Fejes-Toth G (1999) SgK is an aldosterone-induced kinase in the renal collecting duct—effects on epithelial Na+ channels. J Biol Chem 274:16973–16978CrossRefGoogle Scholar
  64. Nielsen S, Chou CL, Marples D, Christensen EI, Kishore BK, Knepper MA (1995) Vasopressin increases water permeability of kidney collecting duct by inducing translocation of aquaporin-CD water channels to plasma membrane. Proc Natl Acad Sci 92:1013–1017PubMedCrossRefGoogle Scholar
  65. Palmer LG, Frindt G (1986) Amiloride-sensitive Na channels from the apical membrane of the rat cortical collecting tubule. Proc Natl Acad Sci 83:2727–2770Google Scholar
  66. Palmer LG, Edelman IS, Lindemann B (1980) Current-voltage analysis of apical sodium transport in toad urinary bladder: effects of inhibitors of transport and metabolism. J Membr Biol 57:59–71PubMedCrossRefGoogle Scholar
  67. Pradervand SP, Barker PM, Wang Q, Ernst SA, Beermann F, Grubb BR, Burnier M, Schmidt A, Bindels RM, Gatzy JT, Rossier BC, Hummler E (1999) Salt restriction induces pseudohypoaldosteronism type 1 in mice expressing low levels of the b-subunit of the amiloride-sensitive epithelial sodium channel. Proc Natl Acad Sci 96:1732–1737PubMedCrossRefGoogle Scholar
  68. Robert-Nicoud M, Flahaut M, Elalouf JM, Nicod M, Salinas M, Bens M, Doucet A, Wincker P, Artiguenave F, Horisberger JD, Vandewalle A, Rossier BC, Firsov D (2001) Transcriptome of a mouse kidney cortical collecting duct cell line: effects of aldosterone and vasopressin. Proc Natl Acad Sci 98:2712–2716PubMedCrossRefGoogle Scholar
  69. Rossier BC, Pradervand SP, Schild L, Hummler E (2002) Epithelial sodium channel and the control of sodium balance: interaction between genetic and environmental factors. Annu Rev Physiol 64:877–897PubMedCrossRefGoogle Scholar
  70. Rubera I, Loffing J, Palmer LG, Frindt G, Fowler-Jaeger N, Sauter D, Carroll T, McMahon A, Hummler E, Rossier BC (2003) Collecting duct-specific gene inactivation of αENaC in the mouse kidney does not impair sodium and potassium balance. J Clin Invest 112:554–565PubMedCrossRefGoogle Scholar
  71. Schaedel C, Marthinsen L, Kristoffersson AC, Kornfalt R, Nilsson KO, Orlenius B, Holmberg L (1999) Lung symptoms in pseudohypoaldosteronism type 1 are associated with deficiency of the α-subunit of the epithelial sodium channel. J Pediatr 135:739–745PubMedCrossRefGoogle Scholar
  72. Schild L, Canessa CM, Shimkets RA, Gautschi I, Lifton RP, Rossier BC (1995) A mutation in the epithelial sodium channel causing Liddle disease increases channel activity in the Xenopus laevis oocyte expression system. Proc Natl Acad Sci 92:5699–5703PubMedCrossRefGoogle Scholar
  73. Shimkets RA, Warnock DG, Bositis CM, Nelson-Williams C, Hansson JH, Schambelan M, Gill JR Jr, Ulick S, Milora RV, Findling JW, Canessa CM, Rossier BC, Lifton RP (1994) Liddle’s syndrome: heritable human hypertension caused by mutations in the b subunit of the epithelial sodium channel. Cell 79:407–414PubMedCrossRefGoogle Scholar
  74. Snyder PM, Price MP, McDonald FJ, Adams CM, Volk KA, Zeiher BG, Stokes JB, Welsh MJ (1995) Mechanism by which Liddle’s syndrome mutations increase activity of a human epithelial Na+ channel. Cell 83:969–978PubMedCrossRefGoogle Scholar
  75. Snyder PM, Bucher DB, Olson DR (2000) Gating induces a conformational change in the outer vestibule of ENaC. J Gen Physiol 116:781–790PubMedCrossRefGoogle Scholar
  76. Snyder PM, Olson DR, Thomas BC (2002) Serum and glucocorticoid-regulated kinase modulates Nedd4-2-mediated inhibition of the epithelial Na+ channel. J Biol Chem 277:5–8PubMedCrossRefGoogle Scholar
  77. Staub O, Gautschi I, Ishikawa T, Breitschopf K, Ciechanover A, Schild L, Rotin D (1997) Regulation of stability and function of the epithelial Na channel ENaC by ubiquitination. EMBO J 16:6325–6336PubMedCrossRefGoogle Scholar
  78. Staub O, Dho S, Henry PC, Correa J, Ishikawa T, McGlade J, Rotin D (1996) WW domains of Nedd4 bind to the proline-rich PY motifs in the epithelial Na+ channel deleted in Liddle’s syndrome. EMBO J 15:2371–2380PubMedGoogle Scholar
  79. Talbot CL, Bosworth DG, Briley EL, Fenstermacher DA, Boucher RC, Gabriel SE, Barker PM (1999) Quantitation and localization of ENaC subunit expression in fetal, newborn, and adult mouse lung. Am J Respir Cell Mol Biol 20: 398–406PubMedGoogle Scholar
  80. van Balkom BW, Graat MP, van Raak M, Hofman E, van der Sluijs SP, Deen PM (2004) Role of cytoplasmic termini in sorting and shuttling of the aquaporin-2 water channel. Am J Physiol Cell Physiol 286:C372–C379PubMedCrossRefGoogle Scholar
  81. Verrey F, Hummler E, Schild L, Rossier BC (2001) Control of Na+ transport by aldosterone. In: Seldin DW, Giebisch G (eds) The kidney. Lippincott, Philadelphia, pp 1441–1472Google Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  1. 1.Department of Pharmacology and ToxicologyUniversity of LausanneLausanneSwitzerland

Personalised recommendations