Advertisement

Function and regulation of claudins in the thick ascending limb of Henle

  • Dorothee Günzel
  • Alan S. L. YuEmail author
Transport Physiology

Abstract

The thick ascending limb (TAL) of Henle mediates transcellular reabsorption of NaCl while generating a lumen-positive voltage that drives passive paracellular reabsorption of divalent cations. Disturbance of paracellular reabsorption leads to Ca2+ and Mg2+ wasting in patients with the rare inherited disorder of familial hypercalciuric hypomagnesemia with nephrocalcinosis (FHHNC). Recent work has shown that the claudin family of tight junction proteins form paracellular pores and determine the ion selectivity of paracellular permeability. Importantly, FHHNC has been found to be caused by mutations in two of these genes, claudin-16 and claudin-19, and mice with knockdown of claudin-16 reproduce many of the features of FHHNC. Here, we review the physiology of TAL ion transport, present the current view of the role and mechanism of claudins in determining paracellular permeability, and discuss the possible pathogenic mechanisms responsible for FHHNC.

Keywords

Channels Ca2+ Conductance Conductance scanning Epithelial transport Ion transport Membrane transport Magnesium Renal Urine 

Notes

Acknowledgments

Work from our own groups that is cited here was supported by the German Research Foundation grant GU447/11-1 (to D.G.) and the National Institutes of Health grant DK062283 (to A.Y.).

References

  1. 1.
    Abuazza G, Becker A, Williams SS et al (2006) Claudins 6, 9, and 13 are developmentally expressed renal tight junction proteins. Am J Physiol Renal Physiol 291:F1132–F1141PubMedCrossRefGoogle Scholar
  2. 2.
    Amasheh S, Meiri N, Gitter AH et al (2002) Claudin-2 expression induces cation-selective channels in tight junctions of epithelial cells. J Cell Sci 115:4969–4976PubMedCrossRefGoogle Scholar
  3. 3.
    Anderson JM, Van Itallie CM, Fanning AS (2004) Setting up a selective barrier at the apical junction complex. Curr Opin Cell Biol 16:140–145PubMedCrossRefGoogle Scholar
  4. 4.
    Angelow S, Yu ASL (2007) Claudins and paracellular transport: an update. Curr Opin Nephrol Hypertens 16:459–464PubMedCrossRefGoogle Scholar
  5. 5.
    Angelow S, El-Husseini R, Kanzawa SA et al (2007) Renal localization and function of the tight junction protein, claudin-19. Am J Physiol Renal Physiol 293:F166–F177PubMedCrossRefGoogle Scholar
  6. 6.
    Angelow S, Schneeberger EE, Yu AS (2007) Claudin-8 expression in renal epithelial cells augments the paracellular barrier by replacing endogenous claudin-2. J Membr Biol 215:147–159PubMedCrossRefGoogle Scholar
  7. 7.
    Ben-Yosef T, Belyantseva IA, Saunders TL et al (2003) Claudin 14 knockout mice, a model for autosomal recessive deafness DFNB29, are deaf due to cochlear hair cell degeneration. Hum Mol Genet 12:2049–2061PubMedCrossRefGoogle Scholar
  8. 8.
    Blanchard A, Jeunemaitre X, Coudol P et al (2001) Paracellin-1 is critical for magnesium and calcium reabsorption in the human thick ascending limb of Henle. Kidney Int 59:2206–2215PubMedGoogle Scholar
  9. 9.
    Bourdeau JE, Burg MB (1979) Voltage dependence of calcium transport in the thick ascending limb of Henle’s loop. Am J Physiol 236:F357–F364PubMedGoogle Scholar
  10. 10.
    Burg M, Good D (1983) Sodium chloride coupled transport in mammalian nephrons. Annu Rev Physiol 45:533–547PubMedCrossRefGoogle Scholar
  11. 11.
    Burg MB, Green N (1973) Function of the thick ascending limb of Henle’s loop. Am J Physiol 224:659–668PubMedGoogle Scholar
  12. 12.
    Claude P, Goodenough DA (1973) Fracture faces of zonulae occludentes from “tight” and “leaky” epithelia. J Cell Biol 58:390–400PubMedCrossRefGoogle Scholar
  13. 13.
    Cole DEC, Quamme GA (2000) Inherited disorders of renal magnesium handling. J Am Soc Nephrol 11:1937–1947PubMedGoogle Scholar
  14. 14.
    Colegio OR, Van Itallie CM, McCrea HJ et al (2002) Claudins create charge-selective channels in the paracellular pathway between epithelial cells. Am J Physiol Cell Physiol 283:C142–C147PubMedGoogle Scholar
  15. 15.
    Dai L-J, Ritchie G, Kerstan D et al (2001) Magnesium transport in the renal distal convoluted tubule. Physiol Rev 81:51–84PubMedGoogle Scholar
  16. 16.
    de Rouffignac C, Quamme G (1994) Renal magnesium handling and its hormonal control. Physiol Rev 74:305–322PubMedGoogle Scholar
  17. 17.
    Di Stefano A, Roinel N, de Rouffignac C et al (1993) Transepithelial Ca2+ and Mg2+ transport in the cortical thick ascending limb of Henle’s loop of the mouse is a voltage-dependent process. Ren Physiol Biochem 16:157–166PubMedGoogle Scholar
  18. 18.
    Eisenman G (1962) Cation selective glass electrodes and their mode of operation. Biophys J 2:259–323PubMedCrossRefGoogle Scholar
  19. 19.
    Enck AH, Berger UV, Yu AS (2001) Claudin-2 is selectively expressed in proximal nephron in mouse kidney. Am J Physiol Renal Physiol 281:F966–F974PubMedGoogle Scholar
  20. 20.
    Friedman PA (1988) Basal and hormone activated calcium absorption in mouse renal thick ascending limbs. Am J Physiol 254:F62–F70PubMedGoogle Scholar
  21. 21.
    Fromm M, Palant CE, Bentzel CJ et al (1985) Protamine reversibly decreases paracellular cation permeability in Necturus gallbladder. J Membr Biol 87:141–150PubMedCrossRefGoogle Scholar
  22. 22.
    Fromm M, Schulzke JD, Hegel U (1985) Epithelial and subepithelial contributions to transmural electrical resistance of intact rat jejunum, in vitro. Pflügers Arch 405:400–402PubMedCrossRefGoogle Scholar
  23. 23.
    Furuse M, Fujita K, Hiiragi T et al (1998) Claudin-1 and -2: novel integral membrane proteins localizing at tight junctions with no sequence similarity to occludin. J Cell Biol 141:1539–1550PubMedCrossRefGoogle Scholar
  24. 24.
    Furuse M, Sasaki H, Tsukita S (1999) Manner of interaction of heterogeneous claudin species within and between tight junction strands. J Cell Biol 147:891–903PubMedCrossRefGoogle Scholar
  25. 25.
    Furuse M, Furuse K, Sasaki H et al (2001) Conversion of zonulae occludentes from tight to leaky strand type by introducing claudin-2 into Madin–Darby canine kidney I cells. J Cell Biol 153:263–272PubMedCrossRefGoogle Scholar
  26. 26.
    Gitelman HJ, Graham JB, Welt LG (1966) A new familial disorder characterized by hypokalemia and hypomagnesemia. Trans Assoc Am Physicians 79:221–235PubMedGoogle Scholar
  27. 27.
    Gitter AH, Bertog M, Schulzke JD et al (1997) Measurement of paracellular epithelial conductivity by conductance scanning. Pflügers Arch 434:830–840PubMedCrossRefGoogle Scholar
  28. 28.
    Gitter AH, Schulzke JD, Sorgenfrei D et al (1997) Ussing chamber for high-frequency transmural impedance analysis of epithelial tissues. J Biochem Biophys Meth 35:81–88PubMedCrossRefGoogle Scholar
  29. 29.
    Gonzalez-Mariscal L, Namorado Mdel C, Martin D et al (2006) The tight junction proteins claudin-7 and -8 display a different subcellular localization at Henle’s loops and collecting ducts of rabbit kidney. Nephrol Dial Transplant 21:2391–2398PubMedCrossRefGoogle Scholar
  30. 30.
    Greger R (1981) Cation selectivity of the isolated perfused cortical thick ascending limb of Henle’s loop of rabbit kidney. Pflügers Arch 390:30–37PubMedCrossRefGoogle Scholar
  31. 31.
    Greger R (1981) Chloride reabsorption in the rabbit cortical thick ascending limb of the loop of Henle. A Sodium Dependent Process. Pflügers Arch 390:38–43PubMedCrossRefGoogle Scholar
  32. 32.
    Günzel D, Stuiver M, Kausalya PJ et al (2007) Functional characterization of claudin-10 isoforms. Acta Physiol 189 Suppl 653:151Google Scholar
  33. 33.
    Hebert SC (2004) Calcium and salinity sensing by the thick ascending limb: a journey from mammals to fish and back again. Kidney Int 91(66 Suppl):S28–S33CrossRefGoogle Scholar
  34. 34.
    Hirano T, Kobayashi N, Itoh T et al (2000) Null mutation of PCLN-1/Claudin-16 results in bovine chronic interstitial nephritis. Genome Res 10:659–663PubMedCrossRefGoogle Scholar
  35. 35.
    Hou J, Paul DL, Goodenough DA (2005) Paracellin-1 and the modulation of ion selectivity of tight junctions. J Cell Sci 118:5109–5118PubMedCrossRefGoogle Scholar
  36. 36.
    Hou J, Shan Q, Wang T et al (2007) Transgenic RNAi depletion of claudin-16 and the renal handling of magnesium. J Biol Chem 282:17114–17122PubMedCrossRefGoogle Scholar
  37. 37.
    Hou J, Renigunta A, Konrad M et al (2008) Claudin-16 and claudin-19 interact and form a cation-selective tight junction complex. J Clin Invest 118:619–628PubMedGoogle Scholar
  38. 38.
    Huang C, Miller RT (2007) Regulation of renal ion transport by the calcium-sensing receptor: an update. Curr Opin Nephrol Hypertens 16:437–443PubMedCrossRefGoogle Scholar
  39. 39.
    Ikari A, Hirai N, Shiroma M et al (2004) Association of paracellin-1 with ZO-1 augments the reabsorption of divalent cations in renal epithelial cells. J Biol Chem 279:54826–54832PubMedCrossRefGoogle Scholar
  40. 40.
    Ikari A, Matsumoto S, Harada H et al (2006) Phosphorylation of paracellin-1 at Ser217 by protein kinase A is essential for localization in tight junctions. J Cell Sci 119:1781–1789PubMedCrossRefGoogle Scholar
  41. 41.
    Ikari A, Okude C, Sawada H et al (2008) Activation of a polyvalent cation-sensing receptor decreases magnesium transport via claudin-16. Biochim Biophys Acta 1778:283–290PubMedCrossRefGoogle Scholar
  42. 42.
    Jensen PK, Fisher RS, Spring KR (1984) Feedback inhibition of NaCI entry in Necturus gallbladder epithelial cells. J Membrane Biol 82:95–104CrossRefGoogle Scholar
  43. 43.
    Kausalya PJ, Amasheh S, Günzel D et al (2006) Disease-associated mutations affect intracellular traffic and paracellular Mg2+ transport function of claudin-16. J Clin Invest 116:878–891PubMedCrossRefGoogle Scholar
  44. 44.
    Kehres DG, Maguire ME (2002) Structure, properties and regulation of magnesium transport proteins. BioMetals 15:261–270PubMedCrossRefGoogle Scholar
  45. 45.
    Kimizuka H, Koketsu K (1964) Ion transport through cell membrane. J Theoret Biol 6:290–305CrossRefGoogle Scholar
  46. 46.
    Kiuchi-Saishin Y, Gotoh S, Furuse M et al (2002) Differential expression patterns of claudins, tight junction membrane proteins, in mouse nephron segments. J Am Soc Nephrol 13:875–886PubMedGoogle Scholar
  47. 47.
    Kleta R, Bockenhauer D (2006) Bartter syndromes and other salt-losing tubulopathies. Nephron Physiol 104:73–80CrossRefGoogle Scholar
  48. 48.
    Köckerling A, Fromm M (1993) Origin of cAMP dependent Cl secretion from both crypts and surface epithelia of rat intestine. Am J Physiol 264:C1294–C1301PubMedGoogle Scholar
  49. 49.
    Konrad M, Weber S (2003) Recent advances in molecular genetics of hereditary magnesium-losing disorders. J Am Soc Nephrol 14:249–260PubMedCrossRefGoogle Scholar
  50. 50.
    Konrad M, Schaller A, Seelow D et al (2006) Mutations in the tight-junction gene claudin 19 (CLDN19) are associated with renal magnesium wasting, renal failure, and severe ocular involvement. Am J Hum Genet 79:949–957PubMedCrossRefGoogle Scholar
  51. 51.
    Konrad M, Hou J, Weber S et al (2008) CLDN16 genotype predicts renal decline in familial hypomagnesemia with hypercalciuria and nephrocalcinosis. J Am Soc Nephrol 19:171–181PubMedCrossRefGoogle Scholar
  52. 52.
    Krämer BK, Bergler T, Stoelcker B et al (2008) Mechanisms of disease: the kidney-specific chloride channels ClCKA and ClCKB, the Barttin subunit, and their clinical relevance. Nature Clin Prac Nephrol 4:38–46CrossRefGoogle Scholar
  53. 53.
    Landau D (2006) Potassium-related inherited tubulopathies. Cell Mol Life Sci 63:1962–1968PubMedCrossRefGoogle Scholar
  54. 54.
    Lee NP, Tong MK, Leung PP et al (2006) Kidney claudin-19: localization in distal tubules and collecting ducts and dysregulation in polycystic renal disease. FEBS Lett 580:923–931PubMedCrossRefGoogle Scholar
  55. 55.
    Li WY, Huey CL, Yu AS (2004) Expression of claudin-7 and -8 along the mouse nephron. Am J Physiol Renal Physiol 286:F1063–F1071PubMedCrossRefGoogle Scholar
  56. 56.
    Madara JL, Dharmsathaphorn K (1985) Occluding junction structure–function relationships in a cultured epithelial monolayer. J Cell Biol 101:2124–2133PubMedCrossRefGoogle Scholar
  57. 57.
    Mandon B, Siga E, Roinel N et al (1993) Ca2+, Mg2+ and K+ transport in the cortical and medullary thick ascending limb of the rat nephron: influence of transepithelial voltage. Pflügers Arch 424:558–560PubMedCrossRefGoogle Scholar
  58. 58.
    Martin RB (1990) Bioinorganic chemistry of magnesium. In: Sigel H, Sigel A (eds) Metal ions in biological systems vol 26. Marcell Dekker, New York, pp 1–13Google Scholar
  59. 59.
    Martinez-Palomo A, Meza I, Beaty G et al (1980) Experimental modulation of occluding junctions in a cultured transporting epithelium. J Cell Biol 87:736–745PubMedCrossRefGoogle Scholar
  60. 60.
    Meij IC, van den Heuvel LP, Knoers NV (2002) Genetic disorders of magnesium homeostasis. BioMetals 15:297–307PubMedCrossRefGoogle Scholar
  61. 61.
    Møllgård K, Malinowski DN, Saunders NR (1976) Lack of correlation between tight junction morphology and permeability properties in developing choroid plexus. Nature 264:293–294CrossRefGoogle Scholar
  62. 62.
    Müller D, Kausalya PJ, Claverie-Martin F et al (2003) A novel claudin-16 mutation associated with childhood hypercalciuria abolishes binding to ZO-1 and results in lysosomal mistargeting. Am J Hum Genet 73:293–1301CrossRefGoogle Scholar
  63. 63.
    Müller D, Kausalya JP, Meij IC et al (2006) Familial hypomagnesemia with hypercalciuria and nephrocalcinosis: blocking endocytosis restores surface expression of a novel Claudin-16 mutant that lacks the entire C-terminal cytosolic tail. Hum Mol Genet 91:3076–3079Google Scholar
  64. 64.
    Nightingale ER Jr (1959) Phenomenological theory of ion solvation. Effective radii of hydrated ions. J Phys Chem 63:1381–1387CrossRefGoogle Scholar
  65. 65.
    Ohta H, Adachi H, Takiguchi M et al (2006) Restricted localization of claudin-16 at the tight junction in the thick ascending limb of Henle’s loop together with claudins 3, 4, and 10 in bovine nephrons. J Vet Med Sci 68:453–463PubMedCrossRefGoogle Scholar
  66. 66.
    Okada K, Ishikawa N, Fujimori K et al (2005) Abnormal development of nephrons in claudin-16-defective Japanese black cattle. J Vet Med Sci 67:171–178PubMedCrossRefGoogle Scholar
  67. 67.
    Pappenheimer JR, Renkin EM, Borrero LM (1951) Filtration, diffusion and molecular sieving through peripheral capillary membranes. A contribution to the pore theory of capillary permeability. Am J Physiol 167:13–46PubMedGoogle Scholar
  68. 68.
    Piontek J, Winkler L, Wolburg H et al (2008) Formation of tight junction: determinants of homophilic interaction between classic claudins. FASEB J 22:146–158PubMedCrossRefGoogle Scholar
  69. 69.
    Praga MJ, Vara E, Gonzalez-Parra A et al (1995) Familial hypomagnesemia with hypercalciuria and nephrocalcinosis. Kidney Int 47:1419–1425PubMedCrossRefGoogle Scholar
  70. 70.
    Rocha AS, Magaldi JB, Kokko JP (1977) Calcium and phosphate transport in isolated segments of rabbit Henle’s loop. J Clin Invest 59:975–983PubMedCrossRefGoogle Scholar
  71. 71.
    Rodríguez- Soriano J (1998) Bartter and related syndromes: the puzzle is almost solved. Pediatr Nephrol 12:315–327PubMedCrossRefGoogle Scholar
  72. 72.
    Rodriguez-Soriano J, Vallo A, Garcia-Fuentes M (1987) Hypomagnesaemia of hereditary renal origin. Pediatr Nephrol 1:465–472PubMedCrossRefGoogle Scholar
  73. 73.
    Satoh J, Romero MF (2002) Mg2+ transport in the kidney. BioMetals 15:285–295PubMedCrossRefGoogle Scholar
  74. 74.
    Schlingmann KP, Konrad M, Seyberth HW (2004) Genetics of hereditary disorders of magnesium homeostasis. Pediatr Nephrol 19:13–25PubMedCrossRefGoogle Scholar
  75. 75.
    Schmitz H, Barmeyer C, Fromm M et al (1999) Altered tight junction structure contributes to the impaired epithelial barrier function in ulcerative colitis. Gastroenterology 116:301–309PubMedCrossRefGoogle Scholar
  76. 76.
    Schultz SG, Solomon AK (1961) Determination of the effective hydrodynamic radii of small molecules by viscometry. J Gen Physiol 44:1189–1199PubMedCrossRefGoogle Scholar
  77. 77.
    Schulzke JD, Bentzel CJ, Schulzke I et al (1998) Epithelial tight junction structure in the jejunum of children with acute and treated celiac sprue. Pediatric Res 43:435–441CrossRefGoogle Scholar
  78. 78.
    Simon DB, Lu Y, Choate KA et al (1999) Paracellin-1, a renal tight junction protein required for paracellular Mg2+ resorption. Science 285:103–106PubMedCrossRefGoogle Scholar
  79. 79.
    Stein WD (1990) Channels, carriers, and pumps: an introduction to membrane transport. Academic, San DiegoGoogle Scholar
  80. 80.
    Stevenson BR, Anderson JM, Goodenough DA et al (1988) Tight junction structure and ZO-1 content are identical in two strains of Madin–Darby canine kidney cells which differ in transepithelial resistance. J Cell Biol. 107:2401–2408PubMedCrossRefGoogle Scholar
  81. 81.
    Suki WN, Rouse D, Ng R et al (1980) Calcium transport in the thick ascending limb of Henle. J Clin Invest 66:1004–1009PubMedCrossRefGoogle Scholar
  82. 82.
    Tang VW, Goodenough DA (2003) Paracellular ion channel at the tight junction. Biophys J 84:1660–1673PubMedCrossRefGoogle Scholar
  83. 83.
    Van Itallie CM, Anderson JM (2006) Claudins and epithelial paracellular transport. Annu Rev Physiol 68:403–429PubMedCrossRefGoogle Scholar
  84. 84.
    Van Itallie CM, Fanning AS, Anderson JM (2003) Reversal of charge selectivity in cation or anion-selective epithelial lines by expression of different claudins. Am J Physiol Renal Physiol 285:F1078–F1084PubMedGoogle Scholar
  85. 85.
    Van Itallie CM, Rogan S, Yu AS et al (2006) Two splice variants of claudin-10 in the kidney create paracellular pores with different ion selectivities. Am J Physiol Renal Physiol 291:F1288–F1299PubMedCrossRefGoogle Scholar
  86. 86.
    Van Itallie CM, Holmes J, Bridges A et al (2008) The density of small tight junction pores varies among cell types and is increased by expression of claudin-2. J Cell Sci 121:298–305PubMedCrossRefGoogle Scholar
  87. 87.
    Ward DT (2004) Calcium receptor-mediated intracellular signalling. Cell Calcium 35:217–228PubMedCrossRefGoogle Scholar
  88. 88.
    Watson CJ, Rowland M, Warhurst G (2001) Functional modeling of tight junctions in intestinal cell monolayers using polyethylene glycol oligomers. Am J Physiol Cell Physiol 281:C388–C397PubMedGoogle Scholar
  89. 89.
    Weber S, Hoffmann K, Jeck N et al (2000) Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis maps to chromosome 3q27 and is associated with mutations in the PCLN-1 gene. Eur J Hum Genet 8:414–422PubMedCrossRefGoogle Scholar
  90. 90.
    Weber S, Schneider L, Peters M et al (2001) Novel paracellin-1 mutations in 25 families with familial hypomagnesemia with hypercalciuria and nephrocalcinosis. J Am Soc Nephrol 12:1872–1881PubMedGoogle Scholar
  91. 91.
    Weber S, Schlingmann KP, Peters M et al (2001) Primary gene structure and expression studies of rodent paracellin-1. J Am Soc Nephrol 12:2664–2672PubMedGoogle Scholar
  92. 92.
    Wittner M, Desfleurs E, Pajaud S et al (1996) Calcium and magnesium: low passive permeability and tubular secretion in the mouse medullary thick ascending limb of Henle’s loop (MTAL). J Membr Biol 153:27–35PubMedCrossRefGoogle Scholar
  93. 93.
    Yu ASL, Enck AH, Lencer WI et al (2003) Claudin-8 expression in Madin–Darby canine kidney cells augments the paracellular barrier to cation permeation. J Biol Chem 278:17350–17359PubMedCrossRefGoogle Scholar
  94. 94.
    Zeissig S, Bürgel N, Günzel D et al (2007) Changes in expression and distribution of claudin-2, -5 and -8 lead to discontinuous tight junctions and barrier dysfunction in active Crohn’s disease. Gut 56:61–72PubMedCrossRefGoogle Scholar
  95. 95.
    Zhao L, Yaoita E, Nameta M et al (2008) Claudin-6 localized in tight junctions of rat podocytes. Am J Physiol Regul Integr Comp Physiol 294:R1856–R1862PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  1. 1.Department of Clinical PhysiologyCharité, Campus Benjamin FranklinBerlinGermany
  2. 2.Division of NephrologyUniversity of Southern California Keck School of MedicineLos AngelesUSA

Personalised recommendations