Abstract
The renal proximal tubule achieves the majority of renal water and solute reabsorption with the help of paracellular channels which lead through the tight junction. The proteins forming such channels in the proximal tubule are claudin-2, claudin-10a, and possibly claudin-17. Claudin-2 forms paracellular channels selective for small cations like Na+ and K+. Independently of each other, claudin-10a and claudin-17 form anion-selective channels. The claudins form the paracellular “pore pathway” and are integrated, together with purely sealing claudins and other tight junction proteins, in the belt of tight junction strands surrounding the tubular epithelial cells. In most species, the proximal tubular tight junction consists of only 1–2 (pars convoluta) to 3–5 (pars recta) horizontal strands. Even so, they seal the tubule very effectively against leak passage of nutrients and larger molecules. Remarkably, claudin-2 channels are also permeable to water so that 20–25% of proximal water absorption may occur paracellularly. Although the exact structure of the claudin-2 channel is still unknown, it is clear that Na+ and water share the same pore. Already solved claudin crystal structures reveal a characteristic β-sheet, comprising β-strands from both extracellular loops, which is anchored to a left-handed four-transmembrane helix bundle. This allowed homology modeling of channel-forming claudins present in the proximal tubule. The surface of cation- and anion-selective claudins differ in electrostatic potentials in the area of the proposed ion channel, resulting in the opposite charge selectivity of these claudins. Presently, while models of the molecular structure of the claudin-based oligomeric channels have been proposed, its full understanding has only started.
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References
Abuazza G, Becker A, Williams SS, Chakravarty S, Truong HT, Lin F, Baum M (2006) Claudins 6, 9, and 13 are developmentally expressed renal tight junction proteins. Am J Physiol Ren Physiol 291:F1132–F1141
Agre P, Preston GM, Smith BL, Jung JS, Raina S, Moon C, Guggino WB, Nielsen S (1993) Aquaporin CHIP: the archetypal molecular water channel. Am J Phys 265:F463–F476
Amasheh S, Meiri N, Gitter AH, Schöneberg T, Mankertz J, Schulzke JD, Fromm M (2002) Claudin-2 expression induces cation-selective channels in tight junctions of epithelial cells. J Cell Sci 115:4969–4976
Anderson JM, Van Itallie CM, Fanning AS (2004) Setting up a selective barrier at the apical junction complex. Curr Opin Cell Biol 16:140–145
Angelow S, Yu AS (2009) Structure-function studies of claudin extracellular domains by cysteine-scanning mutagenesis. J Biol Chem 284:29205–29217
Aronson PS, Giebisch G (1997) Mechanisms of chloride transport in the proximal tubule. Am J Phys 273:F179–F192
Barratt LJ, Rector FC Jr, Kokko JP, Seldin DW (1974) Factors governing the transepithelial potential difference across the proximal tubule of the rat kidney. J Clin Invest 53:454–464
Boulpaep EL (1971) Electrophysiological properties of the proximal tubule: importance of cellular and intercellular transport pathways. In: Giebisch G (ed) Electrophysiology of epithelial cells. Schattauer Verlag, Stuttgart, pp 98–112
Brandner JM, McIntyre M, Kief S, Wladykowski E, Moll I (2003) Expression and localization of tight junction-associated proteins in human hair follicles. Arch Dermatol Res 295:211–221
Branton D, Bullivant S, Gilula NB, Karnovsky MJ, Moor H, Mühlethaler K, Northcote DH, Packer L, Satir B, Satir P, Speth V, Staehlin LA, Steere RL, Weinstein RS (1975) Freeze-etching nomenclature. Science (New York, NY) 190:54–56
Cheval L, Pierrat F, Dossat C, Genete M, Imbert-Teboul M, Duong Van Huyen J-P, Poulain J, Wincker P, Weissenbach J, Piquemal D, Doucet A (2011) Atlas of gene expression in the mouse kidney: new features of glomerular parietal cells. Physiol Genomics 43:161–173
Claude P (1978) Morphological factors influencing transepithelial permeability: a model for the resistance of the Zonula Occludens. J Membr Biol 39:219–232
Claude P, Goodenough DA (1973) Fracture faces of zonulae occludentes from “tight” and “leaky” epithelia. J Cell Biol 58:390–400
Conrad MP, Piontek J, Günzel D, Fromm M, Krug SM (2016) Molecular basis of claudin-17 anion selectivity. Cell Mol Life Sci 73:185–200
Diamond JM (1978) Channels in epithelial cell membranes and junctions. Fed Proc 37:2639–2643
Diamond JM (1974) Tight and leaky junctions of epithelia: a perspective on kisses in the dark. Fed Proc 33:2220–2224
Duarte CG, Watson JF (1967) Calcium reabsorption in proximal tubule of the dog nephron. Am J Phys 212:1355–1360
Eichner M, Protze J, Piontek A, Krause G, Piontek J (2017) Targeting and alteration of tight junctions by bacteria and their virulence factors such as Clostridium perfringens enterotoxin. Pflügers Arch Eur J Physiol 469:77–90
Elkouby-Naor L, Abassi Z, Lagziel A, Gow A, Ben-Yosef T (2008) Double gene deletion reveals lack of cooperation between claudin 11 and claudin 14 tight junction proteins. Cell Tissue Res 333:427–438
Enck AH, Berger UV, Yu AS (2001) Claudin-2 is selectively expressed in proximal nephron in mouse kidney. Am J Physiol Ren Physiol 281:966–974
Farquhar MG, Palade GE (1963) Junctional complexes in various epithelia. J Cell Biol 17:375–412
France MM, Turner JR (2017) The mucosal barrier at a glance. J Cell Sci 130:307–314
Fujita H, Sugimoto K, Inatomi S, Maeda T, Osanai M, Uchiyama Y, Yamamoto Y, Wada T, Kojima T, Yokozaki H, Yamashita T, Kato S, Sawada N, Chiba H (2008) Tight junction proteins claudin-2 and -12 are critical for vitamin D-dependent Ca2+ absorption between enterocytes. Mol Biol Cell 19:1912–1921
Furuse M, Fujita K, Hiiragi T, Fujimoto K, Tsukita S (1998) Claudin-1 and -2: novel integral membrane proteins localizing at tight junctions with no sequence similarity to occludin. J Cell Biol 141:1539–1550
Furuse M, Furuse K, Sasaki H, Tsukita S (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 153:263–272
Furuse M, Hirase T, Itoh M, Nagafuchi A, Yonemura S, Tsukita S, Tsukita S (1993) Occludin: a novel integral membrane protein localizing at tight junctions. J Cell Biol 123:1777–1788
Furuse M, Sasaki H, Tsukita S (1999) Manner of interaction of heterogeneous claudin species within and between tight junction strands. J Cell Biol 147:891–903
Gong Y, Renigunta V, Zhou Y, Sunq A, Wang J, Yang J, Renigunta A, Baker LA, Hou J (2015) Biochemical and biophysical analyses of tight junction permeability made of claudin-16 and claudin-19 dimerization. Mol Biol Cell 26:4333–4346
Günzel D, Fromm M (2012) Claudins and other tight junction proteins. Compr Physiol 2:1819–1852
Günzel D, Stuiver M, Kausalya PJ, Haisch L, Krug SM, Rosenthal R, Meij IC, Hunziker W, Fromm M, Müller D (2009) Claudin-10 exists in six alternatively spliced isoforms that exhibit distinct localization and function. J Cell Sci 122:1507–1517
Günzel D, Yu AS (2013) Claudins and the modulation of tight junction permeability. Physiol Rev 93:525–569
Guo P, Weinstein AM, Weinbaum S (2003) A dual-pathway ultrastructural model for the tight junction of rat proximal tubule epithelium. Am J Physiol Ren Physiol 285:F241–F257
Haddad M, Lin F, Dwarakanath V, Cordes K, Baum M (2005) Developmental changes in proximal tubule tight junction proteins. Pediatr Res 57:453–457
Ikenouchi J, Furuse M, Furuse K, Sasaki H, Tsukita S, Tsukita S (2005) Tricellulin constitutes a novel barrier at tricellular contacts of epithelial cells. J Cell Biol 171:939–945
Irudayanathan FJ, Trasatti JP, Karande P, Nangia S (2016) Molecular architecture of the blood brain barrier tight junction proteins—a synergistic computational and in vitro approach. J Phys Chem B 120:77–88
Kirk A, Campbell S, Bass P, Mason J, Collins J (2010) Differential expression of claudin tight junction proteins in the human cortical nephron. Nephrol Dial Transplant 25:2107–2119
Kiuchi-Saishin Y, Gotoh S, Furuse M, Takasuga A, Tano Y, Tsukita S (2002) Differential expression patterns of claudins, tight junction membrane proteins, in mouse nephron segments. J Am Soc Nephrol 13:875–886
Krause G, Protze J, Piontek J (2015) Assembly and function of claudins: structure-function relationships based on homology models and crystal structures. Semin Cell Dev Biol 42:3–12
Krug SM (2017) Contribution of the tricellular tight junction to paracellular permeability in leaky and tight epithelia. Ann N Y Acad Sci doi:10.1111/nyas.13379 (in press)
Krug SM, Amasheh M, Dittmann I, Christoffel I, Fromm M, Amasheh S (2013) Sodium caprate as an enhancer of macromolecule permeation across tricellular tight junctions of intestinal cells. Biomaterials 34:275–282
Krug SM, Amasheh S, Richter JF, Milatz S, Günzel D, Westphal JK, Huber O, Schulzke JD, Fromm M (2009) Tricellulin forms a barrier to macromolecules in tricellular tight junctions without affecting ion permeability. Mol Biol Cell 20:3713–3724
Krug SM, Günzel D, Conrad MP, Rosenthal R, Fromm A, Amasheh S, Schulzke JD, Fromm M (2012) Claudin-17 forms tight junction channels with distinct anion selectivity. Cell Mol Life Sci 69:2765–2778
Krug SM, Schulzke JD, Fromm M (2014) Tight junction, selective permeability, and related diseases. Semin Cell Dev Biol 36:166–176
Li J, Zhuo M, Pei L, Rajagopal M, Yu AS (2014) Comprehensive cysteine-scanning mutagenesis reveals Claudin-2 pore-lining residues with different intrapore locations. J Biol Chem 289:6475–6484
Liebner S, Kniesel U, Kalbacher H, Wolburg H (2000) Correlation of tight junction morphology with the expression of tight junction proteins in blood-brain barrier endothelial cells. Eur J Cell Biol 79:707–717
Marcial MA, Carlson SL, Madara JL (1984) Partitioning of paracellular conductance along the ileal crypt-villus axis: a hypothesis based on structural analysis with detailed consideration of tight junction structure-function relationships. J Membr Biol 80:59–70
Martinez-Palomo A, Erlij D (1975) Structure of tight junctions in epithelia with different permeability. Proc Natl Acad Sci U S A 72:4487–4491
Menco BP (1988) Tight-junctional strands first appear in regions where three cells meet in differentiating olfactory epithelium: a freeze-fracture study. J Cell Sci 89(Pt 4):495–505
Milatz S, Breiderhoff T (2017) One gene, two paracellular ion channels—claudin-10 in the kidney. Pflügers Arch Eur J Physiol 469:115–121
Milatz S, Himmerkus N, Wulfmeyer VC, Drewell H, Mutig K, Hou J, Breiderhoff T, Müller D, Fromm M, Bleich M, Günzel D (2017) Mosaic expression of claudins in thick ascending limbs of Henle results in spatial separation of paracellular Na+ and Mg2+ transport. Proc Natl Acad Sci U S A 114:E219–e227
Milatz S, Krug SM, Rosenthal R, Günzel D, Müller D, Schulzke JD, Amasheh S, Fromm M (2010) Claudin-3 acts as a sealing component of the tight junction for ions of either charge and uncharged solutes. Biochim Biophys Acta 1798:2048–2057
Milatz S, Piontek J, Hempel C, Grohe C, Fromm A, Lee IM, El-Athman R, Günzel D (2017) Tight junction strand formation by claudin-10 isoforms and claudin-10a/−10b chimeras. Ann N Y Acad Sci, doi:10.1111/nyas.13393 (in press)
Milatz S, Piontek J, Schulzke JD, Blasig IE, Fromm M, Günzel D (2015) Probing the cis-arrangement of prototype tight junction proteins claudin-1 and claudin-3. Biochem J 468:449–458
Morita K, Furuse M, Fujimoto K, Tsukita S (1999) Claudin multigene family encoding four-transmembrane domain protein components of tight junction strands. Proc Natl Acad Sci U S A 96:511–516
Muto S, Hata M, Taniguchi J, Tsuruoka S, Moriwaki K, Saitou M, Furuse K, Sasaki H, Fujimura A, Imai M, Kusano E, Tsukita S, Furuse M (2010) Claudin-2-deficient mice are defective in the leaky and cation-selective paracellular permeability properties of renal proximal tubules. Proc Natl Acad Sci U S A 107:8011–8016
Pei L, Solis G, Nguyen MT, Kamat N, Magenheimer L, Zhuo M, Li J, Curry J, McDonough AA, Fields TA, Welch WJ, Yu AS (2016) Paracellular epithelial sodium transport maximizes energy efficiency in the kidney. J Clin Invest 126:2509–2518
Piontek A, Rossa J, Protze J, Wolburg H, Hempel C, Günzel D, Krause G, Piontek J (2017) Polar and charged extracellular residues conserved among barrier-forming claudins contribute to tight junction strand formation. Ann N Y Acad Sci, doi:10.1111/nyas.13341 (in press)
Piontek J, Fritzsche S, Cording J, Richter S, Hartwig J, Walter M, Yu D, Turner JR, Gehring C, Rahn HP, Wolburg H, Blasig IE (2011) Elucidating the principles of the molecular organization of heteropolymeric tight junction strands. Cell Mol Life Sci 68:3903–3918
Piontek J, Winkler L, Wolburg H, Müller SL, Zuleger N, Piehl C, Wiesner B, Krause G, Blasig IE (2008) Formation of tight junction: determinants of homophilic interaction between classic claudins. FASEB J 22:146–158
Pricam C, Fisher KA, Friend DS (1977) Intramembranous particle distribution in human erythrocytes: effects of lysis, glutaraldehyde, and poly-L-lysine. Anat Rec 189:595–607
Protze J, Eichner M, Piontek A, Dinter S, Rossa J, Blecharz KG, Vajkoczy P, Piontek J, Krause G (2015) Directed structural modification of Clostridium perfringens enterotoxin to enhance binding to claudin-5. Cell Mol Life Sci 72:1417–1432
Roesinger B, Schiller A, Taugner R (1978) A freeze-fracture study of tight junctions in the pars convoluta and pars recta of the renal proximal tubule. Cell Tissue Res 186:121–133
Rosenthal R, Günzel D, Krug SM, Schulzke JD, Fromm M, Yu AS (2017) Claudin-2-mediated cation and water transport share a common pore. Acta Physiol (Oxford, England) 219:521–536
Rosenthal R, Milatz S, Krug SM, Oelrich B, Schulzke JD, Amasheh S, Günzel D, Fromm M (2010) Claudin-2, a component of the tight junction, forms a paracellular water channel. J Cell Sci 123:1913–1921
Rossa J, Ploeger C, Vorreiter F, Saleh T, Protze J, Günzel D, Wolburg H, Krause G, Piontek J (2014) Claudin-3 and claudin-5 protein folding and assembly into the tight junction are controlled by non-conserved residues in the transmembrane 3 (TM3) and extracellular loop 2 (ECL2) segments. J Biol Chem 289:7641–7653
Rossa J, Protze J, Kern C, Piontek A, Günzel D, Krause G, Piontek J (2014) Molecular and structural transmembrane determinants critical for embedding claudin-5 into tight junctions reveal a distinct four-helix bundle arrangement. Biochem J 464:49–60
Saitoh Y, Suzuki H, Tani K, Nishikawa K, Irie K, Ogura Y, Tamura A, Tsukita S, Fujiyoshi Y (2015) Tight junctions. Structural insight into tight junction disassembly by Clostridium perfringens enterotoxin. Science (New York, NY) 347:775–778
Schiller A, Tiedemann K (1981) The mature mesonephric nephron of the rabbit embryo. III. Freeze-fracture studies. Cell Tissue Res 221:431–442
Schnermann J, Chou CL, Ma T, Traynor T, Knepper MA, Verkman AS (1998) Defective proximal tubular fluid reabsorption in transgenic aquaporin-1 null mice. Proc Natl Acad Sci U S A 95:9660–9664
Schnermann J, Huang Y, Mizel D (2013) Fluid reabsorption in proximal convoluted tubules of mice with gene deletions of claudin-2 and/or aquaporin1. Am J Physiol Ren Physiol 305:F1352–F1364
Seldin DW (1999) Renal handling of calcium. Nephron 81(Suppl 1):2–7
Shen L, Weber CR, Raleigh DR, Yu D, Turner JR (2011) Tight junction pore and leak pathways: a dynamic duo. Annu Rev Physiol 73:283–309
Shinoda T, Shinya N, Ito K, Ohsawa N, Terada T, Hirata K, Kawano Y, Yamamoto M, Kimura-Someya T, Yokoyama S, Shirouzu M (2016) Structural basis for disruption of claudin assembly in tight junctions by an enterotoxin. Sci Rep 6:33632
Staehelin LA (1973) Further observations on the fine structure of freeze-cleaved tight junctions. J Cell Sci 13:763–786
Staehelin LA (1974) Structure and function of intercellular junctions. Int Rev Cytol 39:191–283
Staehelin LA, Mukherjee TM, Williams AW (1969) Freeze-etch appearance of the tight junctions in the epithelium of small and large intestine of mice. Protoplasma 67:165–184
Steed E, Rodrigues NT, Balda MS, Matter K (2009) Identification of MarvelD3 as a tight junction-associated transmembrane protein of the occludin family. BMC Cell Biol 10:95
Suzuki H, Nishizawa T, Tani K, Yamazaki Y, Tamura A, Ishitani R, Dohmae N, Tsukita S, Nureki O, Fujiyoshi Y (2014) Crystal structure of a claudin provides insight into the architecture of tight junctions. Science (New York, NY) 344:304–307
Suzuki H, Tani K, Tamura A, Tsukita S, Fujiyoshi Y (2015) Model for the architecture of claudin-based paracellular ion channels through tight junctions. J Mol Biol 427:291–297
Tőkés A-M, Szász AM, Juhász É, Schaff Z, Harsányi L, Molnár IA, Baranyai Z, Besznyák I, Zaránd A, Salamon F, Kulka J (2012) Expression of tight junction molecules in breast carcinomas analysed by array PCR and immunohistochemistry. Pathol Oncol Res 18:593–606
Van Itallie C, Rahner C, Anderson JM (2001) Regulated expression of claudin-4 decreases paracellular conductance through a selective decrease in sodium permeability. J Clin Invest 107:1319–1327
Van Itallie CM, Holmes J, Bridges A, Gookin JL, Coccaro MR, Proctor W, Colegio OR, Anderson JM (2008) The density of small tight junction pores varies among cell types and is increased by expression of claudin-2. J Cell Sci 121:298–305
Van Itallie CM, Rogan S, Yu A, Vidal LS, Holmes J, Anderson JM (2006) Two splice variants of claudin-10 in the kidney create paracellular pores with different ion selectivities. Am J Physiol Ren Physiol 291:F1288–F1299
Wada M, Tamura A, Takahashi N, Tsukita S (2013) Loss of claudins 2 and 15 from mice causes defects in paracellular Na+ flow and nutrient transport in gut and leads to death from malnutrition. Gastroenterology 144:369–380
Watson CJ, Rowland M, Warhurst G (2001) Functional modeling of tight junctions in intestinal cell monolayers using polyethylene glycol oligomers. Am J Phys Cell Phys 281:C388–C397
Wolburg H, Neuhaus J, Kniesel U, Krauss B, Schmid EM, Ocalan M, Farrell C, Risau W (1994) Modulation of tight junction structure in blood-brain barrier endothelial cells. Effects of tissue culture, second messengers and cocultured astrocytes. J Cell Sci 107(Pt 5):1347–1357
Yu AS, Cheng MH, Angelow S, Günzel D, Kanzawa SA, Schneeberger EE, Fromm M, Coalson RD (2009) Molecular basis for cation selectivity in claudin-2-based paracellular pores: identification of an electrostatic interaction site. J Gen Physiol 133:111–127
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The authors’ work is supported by grants of the Deutsche Forschungsgemeinschaft DFG FR 652/12-1, DFG PI 837/4-1, and DFG GU 447/14-1.
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This article is part of the special issue on Functional Anatomy of the Kidney in Health and Disease in Pflügers Archiv—European Journal of Physiology
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Fromm, M., Piontek, J., Rosenthal, R. et al. Tight junctions of the proximal tubule and their channel proteins. Pflugers Arch - Eur J Physiol 469, 877–887 (2017). https://doi.org/10.1007/s00424-017-2001-3
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DOI: https://doi.org/10.1007/s00424-017-2001-3