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Claudins and the Kidney

Alan S.L. Yu

Division of Nephrology and Hypertension, and the Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas

ABSTRACT Claudins are tight-junction membrane proteins that function as both pores and barriers dimensional structure of claudin-15 has in the paracellular pathway in epithelial cells. In the kidney, claudins determine the recently been solved at a resolution of 2.4 permeability and selectivity of different nephron segments along the renal tubule. In Å.17 The structure reveals a characteris- the proximal tubule, claudins have a role in the bulk reabsorption of salt and water. In the tic b-sheet fold comprising the two ex- thick ascending limb, claudins are important for the reabsorption of calcium and tracellular segments, which is anchored magnesium and are tightly regulated by the calcium-sensing receptor. In the distal to a transmembrane four-helix bundle. nephron, claudins need to form cation barriers and chloride pores to facilitate This b-sheet forms a palm-like region electrogenic sodium reabsorption and potassium and acid secretion. Aldosterone and that likely lines the paracellular pore the with-no-lysine (WNK) proteins likely regulate claudins to fine-tune distal nephron salt (Figure 1). transport. Genetic mutations in claudin-16 and -19 cause familial hypomagnesemic hypercalciuria with nephrocalcinosis, whereas polymorphisms in claudin-14 are associ- ated with kidney stone risk. It is likely that additional roles for claudins in the EXPRESSION OF CLAUDINS IN pathogenesis of other types of kidney diseases have yet to be uncovered. THE KIDNEY

J Am Soc Nephrol 26: 11–19, 2015. doi: 10.1681/ASN.2014030284 Most claudins are expressed in the renal tubule. Each segment and cell expresses multiple isoforms (Figure 2, Table 1). It The renal tubule efficiently reabsorbs the are not completely settled.6,7 Claudin is widely believed that the specificsetof bulk of filtered salt and water, and proteins have four predicted transmem- claudins expressed by each nephron accurately fine-tunes the concentrations brane helical domains with a short in- segment determines the unique paracel- of many different solutes in the urine. tracellular N-terminus, two extracellular lular permeability properties of that seg- This challenging task is accomplished loops, and a long C-terminal tail. Clau- ment. In addition, the glomerulus also by a combination of transcellular and dins are thought to polymerize to form expresses claudins. Parietal epithelial paracellular transport. The paracellular continuous strands along the lateral cells express claudin-1.18,19 Mature po- pathway is a route for passive transport membrane of one cell while the extracel- docytes form slit diaphragms, which that passes between tubule epithelial lular domains of claudins on adjacent are a specialized form of intercellular cells,1 with the tight junction constitut- cells bridge the paracellular space to in- junction, but tight junctions are also ing the primary permeability barrier.2–4 teract with each other, much like the present during fetal development and Claudins are members of a family of teeth of a zipper. The first extracellular reappear during podocyte injury.20,21 tight-junction membrane proteins that loop appears to line the paracellular pore Claudin-5 and -6 have both been detected act simultaneously as paracellular pores and determine its selectivity,8,9 while the in podocytes.22,23 and barriers and determine the selectiv- second extracellular loop mediates trans ity to small ions and neutral solutes.5 interactions.10,11 The C-terminal tail plays roles in protein trafficking to the tight junction and protein stability,12 Published online ahead of print. Publication date available at www.jasn.org. STRUCTURE AND FUNCTION OF contains phosphorylation13 and palmi- CLAUDINS toylation sites,14 and has a conserved hy- Correspondence: Dr. Alan S.L. Yu, Kidney In- stitute, University of Kansas Medical Center, 3901 drophobic dipeptide motif that binds Rainbow Boulevard, 6018 WHE, Kansas City, KS There are 27 mammalian claudin genes, to PDZ domains on tight-junction 66160-3018. Email: [email protected] although the homology and nomencla- scaffolding proteins, including ZO1, Copyright © 2015 by the American Society of ture of the more distantly related genes ZO2, ZO3,15 and MUPP1.16 The three- Nephrology

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erties of the host cell line. For example, reabsorption in the late superficial PT claudin-15 decreases Cl permeability have been well studied37,38 (Figure 3A). when overexpressed in Na-selective, leaky Late PT fluid has relatively high concen- 2 2 MDCK II cells,9 whereas in Cl -selective trations of Cl and low concentrations of 2 and less leaky LLC-PK1 cells, claudin-15 HCO3 because of early PT transcellular increases Na+ permeability.24 reabsorption of Na, coupled largely to 2 In general, claudins regulate a pore HCO3 or organic solutes, together with pathway that is selectively permeable to isosmotic water reabsorption. The late PT 2 2 smallionsandneutralsolutes.Unlikemost is more permeable to Cl than HCO3 transmembrane channels, claudins do not (PCl/PHCO3 ratio ranging from 2 to tend to be highly selective but they do 1839,40). This permits net passive reabsorp- 2 exhibit charge preference. Thus, claudins tion of Cl , presumably via paracellular that are more cation-selective preferen- diffusion, and generates a lumen-positive tially permeate Na+,K+, and other mono- electrical potential.41 This voltage in turn valent cations but also divalent cations provides the driving force for passive reab- such as Ca2+.25,26 Anion-selective claudins sorption of Na+,againpresumablyvia the 2 permeate Cl but also other halides and paracellular pathway. An estimated 32%– small anions.27 Claudins differ in the mag- 64% of superficial PT NaCl reabsorption is nitude of their permeability, with some passive and presumably paracellular (re- predominantly acting as pore-formers viewed in reference 42). and others acting mostly as barrier-formers. Claudin-2 is the main claudin respon- The underlying mechanism for this is sible for reabsorption of Na+. Claudin-2 is Figure 1. Structure of a claudin-15 mono- unknown but likely involves intrinsic highly expressed in the PT,18 with highest mer, viewed from just above the plane of the differences in the size and conformation levels in the late PT and early segment of membrane. Four transmembrane ahelices (blue) traverse the lipid bilayer. The first oftheporeformedbyeachclaudin the thin descending limb of long loops of 43 In vitro 25,26,44 extracellular domain contributes four b isoform. Henle. overexpression 45 strands (yellow) to the b-sheet structure and The pore diameter has been estimated and knockdown studies have shown a short extracellular helix (red), while the for claudin-2 and is 6.5–8Å,26,28 making that claudin-2 forms high-conductance, second extracellular domain contributes it permeable to small organic ions, neu- cation-selective paracellular pores. Muto the fifth b strand (green). The b sheet forms tral molecules, and even water.29 In ad- et al. generated a constitutive knockout an inward-facing palm that likely lines the dition to this pore pathway, the tight of claudin-2 in mice and showed a signif- pore pathway. Image of protein databank junction exhibits a low-capacity, size- icant decrease in net Na and water reab- ID: 4P79 (ref. 17) created with visual mo- independent permeability to uncharged sorption in the PT S2 segments and loss of lecular dynamics 1.9.1 (ref. 115). macromolecules, such as dextrans. The Na+ selectivity.46 The mice had normal latter has been dubbed the “leak path- fractional excretion of Na+ on a normal way”30 and appears to be dependent on diet but had excessive natriuresis in re- IN VITRO PERMEABILITY occludin31,32 and ZO-133 but not on sponse to a saline load. Thus, claudin-2 PROPERTIES OF CLAUDINS claudins. Table 1 summarizes the func- likely plays an important role in PT para- tional properties of claudins of particular cellular salt reabsorption. The function of individual claudins in relevance to the kidney. A more detailed The PT also reabsorbs a substantial determining paracellular permeabilityand and comprehensive catalog of claudins portion of filtered K+47,48 and Ca2+49,50 selectivity has been investigated primarily and their properties may be found in re- and this is thought to be mostly pas- byoverexpression and knockdown experi- cent general reviews.34,35 sive. There are two proposed mecha- ments in epithelial cell lines. The inter- nisms: (1) passive diffusion, driven by a pretation of such studies is complicated lumen-to-bath K+ and Ca2+ concentra- because, unlike transmembrane transport ROLE OF CLAUDINS IN THE tion gradient (generated by net water re- proteins, claudins must simultaneously PROXIMAL TUBULE absorption) and lumen-positive electrical function as both the barrier and the pores. gradient in the mid-late PT, or (2)convection Moreover, all epithelia already express The primary role of the proximal tubule (solvent drag). It has always been assumed multiple endogenous claudins, so the (PT) is bulk reabsorption of filtered sol- (as for NaCl) that the route of this passive 2 function of a heterologously expressed utes, including Na+,K+,Cl ,andCa2+, reabsorption is paracellular, but this has (or a knocked down) claudin gene must and water. The PT is the leakiest neph- never been definitively proven. Claudin-2 be superimposed on this background. As a ron segment in the renal tubule, with is highly permeable to K+ and also mod- consequence, the apparent function of transepithelial resistances of 5–7 V.cm2.36 erately permeable to Ca2+.26 Claudin-2 claudin is highly dependent on the prop- The driving forces for paracellular NaCl null mice do not have any abnormality in

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Figure 2. Localization of claudins along the adult mammalian renal tubule. Captions shaded in gray summarize some of the key physiologic functions of each nephron segment. AVP, arginine vasopressin; TGF, tubuloglomerular feedback. Refer to Table 1 for references.

Table 1. Localization and role of claudins in the mammalian renal tubule Claudin Tubule Localization Permeability Propertiesa Physiologic Rolea 18,43 + + 2+ 25,26,29,44 + 46,62 2 PT, tDL Na ,K ,Ca , and H2O pore PT Na and fluid reabsorption 3 tAL, TALH, DCT, CD18 Nonselective barrier107 Unknown 2 4tAL,CD18 Na+ barrier and Cl pore45,87,108 Facilitates aldosterone-sensitive distal electrogenic Na+ reabsorption?96 2 2 7 tDL, DCT, CD85,109 Cl barrier85,110 or Cl pore?45 Renal salt reabsorption86 8 tDL, DCT, CD18,109 Na+,K+,andH+ barrier88,89and Cl pore108 Facilitates distal electrogenic Na+ reabsorption? 2 2 10a PT, TALH, CCD27,63 Cl pore63 PT Cl reabsorption? 10b TALH, MCD27,63 Na2+ pore63 Unknown 14 TALH81 Na+81or Na+ and Ca2+ barrier82 Mediates CaSR inhibition of TALH Ca2+ and Mg2+ reabsorption81–83 16 tAL, TALH70,111 Na+ 112 or Ca2+ and Mg2+ pore74,75,113 TALH reabsorption of divalent cations72,76 2 2 17 PT . tAL, TALH, DCT64 Cl pore64 PT Cl reabsorption? 18 TALH, CD73 Na+ and H+ barrier114 Unknown 2 19 tAL, TALH71,111 Cl barrier77 TALH reabsorption of divalent cations73 PT, proximal tubule; tDL, thin descending limb; tAL, thin ascending limb; DCT, distal convoluted tubule; CD, collecting duct; CCD, cortical collecting duct; MCD, medullary collecting duct. aQuestion marks indicate speculative conclusions that have not been studied experimentally or for which multiple studies came to different conclusions.

K+ excretion, but they are hypercalciuric,46 found that the reflection coefficient for which has been attributed to entrainment suggesting the possibility that claudin-2 NaCl in the PT is ,1, consistent with a of solute movement with water through may mediate PT paracellular Ca re- convective pathway,53,54 but others have the paracellular shunt.59–61 absorption. not.55,56 Estimates extrapolating from Claudin-2 has now been shown in A long-standing controversy in renal small solute permeabilities have suggested cultured cell monolayers to permeate wa- physiology concerns whether water is that paracellular water permeability is ter,29 providing a potential molecular basis transported paracellularly in the PT.51 At very low,57 whereas those derived from for paracellular water reabsorption in the least 75% of PT water permeability is measurements of plasma membrane wa- PT. Like Muto, Schnermann et al. found a transcellular and mediated by aqua- ter permeability have suggested a large substantial (23%) reduction in proximal porin-1.52 However, the mechanism by contribution from the paracellular path- fractional volume reabsorption in claudin-2 which the remaining 25% is transported way.58 Finally, a number of investigators null mice.62 This could arguably be due is unclear. Several investigators have have observed solvent drag in the PT, to the primary defect in Na reabsorption,

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Figure 3. Physiologic roles of claudins in renal tubule epithelia. (A) Proximal tubule. Na+ reabsorption by Na+-H+ exchange or coupled to 2 organic solutes, such as glucose, generates a high luminal Cl concentration and negative transepithelial voltage that drives paracellular 2 Cl reabsorption. The subsequent lumen-positive voltage drives Na+ reabsorption through claudin-2. (B) Thick ascending limb. Trans- cellular Na reabsorption via the Na-K-2Cl cotransporter with K+ recycling via an apical K+ channel generates a lumen-positive voltage. This is further augmented by the tendency of reabsorbed Na+ to backflux through Na+-selective paracellular pores, postulated to be formed by claudin-16 and -19. This voltage drives Ca2+ and Mg2+ reabsorption paracellularly. The CaSR regulates paracellular transport by a cascade involving calcineurin, micro-RNAs, and claudin-14. (C) Collecting duct. Na+ is reabsorbed electrogenically via an apical epithelial Na+ channel in principal cells. The paracellular pathway, proposed to be constituted by claudin-4, -7, and/or -8, acts as a barrier to prevent 2 backflux of reabsorbed Na+ (as well as secreted K+ and H+) while allowing Cl to diffuse down its electrical gradient. In each panel, the lumen is on the left and peritubular space on the right. which would be expected to reduce the os- cation reabsorption that has recently been presumably reflecting a cation-selective motic gradient for water reabsorption. shown to be highly regulated (Figure 3B). paracellular shunt. The magnitude of However, they found no change in the The driving force for paracellular cation this dilution potential can be appreci- end-proximal transepithelial osmotic gradi- reabsorption is a lumen-positive transepi- ated in isolated TALH tubules in the ab- ent. This suggested that claudin-2 may well thelial voltage. This voltage is generated sence of flow, when transepithelial mediate a portion of PT water reabsorp- primarily by the charge movement associ- voltage can reach 10–25 mV.66,68,69 tion. However, the researchers could not de- ated with transcellular reabsorption of Claudin-16 (originally named para- 2 monstrate an additive effect of claudin-2 NaCl. Na+,K+,andCl enter the cellin-1) and claudin-19 are expressed in and AQP1 knockout on proximal fluid re- TALH cell through the electroneutral the TALH and are clearly required for absorption, as would be expected if they Na-K-2Cl cotransporter at the apical paracellular divalent cation reabsorption. were acting on different routes, so the is- membrane; Na is pumped out through Loss-of-function mutations in either gene 2 sue must be regarded as not yet settled. the Na-K-ATPase, and Cl effluxes cause familial hypomagnesemia with hy- 2 Themoleculesthatmediateparacellular basolaterally via Cl channels; however, percalciuria and nephrocalcinosis Cl reabsorption have not been identified K+ is largely recycled apically via the, (FHHNC) in humans,70,71 while mice yet. Claudin-10a27,63 and claudin-1764 renal outer medullary K+ channel, thus with knockdown of claudin-16 or -19 are both known to form anion-selective generating a lumen-positive electrical have renal Mg2+ and Ca2+ wasting.72,73 paracellular pores and are both expressed potential. At high tubule flow rates, However, the mechanism of action of in the PT, so they are potential candidates this transepithelial electrical potential theseclaudinsiscontroversial.Some for this role. averages 3–10 mV, lumen-positive.65 At investigators found that claudin-16 over- low flow rates, this voltage is augmented expression increased Ca2+ and Mg2+ per- by a superimposed NaCl dilution poten- meability74,75 and that claudin-16 ROLE OF CLAUDINS IN THE THICK tial. This is caused by the generation of a knockout mice have reduced TALH Ca2+ ASCENDING LIMB NaCl concentration gradient (tubule and Mg2+ permeability,76 and argued that lower than interstitium) across the epi- this claudin forms the TALH paracellular 2 The thick ascending limbofHenle (TALH) thelium, which has a Na+ to Cl perme- Ca2+ and Mg2+ pore itself. By contrast, 66–68 isanimportantsitefor paracellulardivalent ability ratio (PNa/PCl)of2–6, Hou et al. found that claudin-16 primarily

14 Journal of the American Society of Nephrology J Am Soc Nephrol 26: 11–19, 2015 www.jasn.org BRIEF REVIEW increased Na permeability while claudin- ROLE OF CLAUDINS IN THE and they develop urothelial hyperplasia 19 decreased Cl permeability, and that ALDOSTERONE-SENSITIVE DISTAL and hydronephrosis as they get older. they interacted with each other in order NEPHRON to traffic correctly to the tight junc- tion.73,77 They have proposed that the The aldosterone-sensitive distal nephron REGULATION OF ASDN CLAUDINS primary role of these genes is to in- (ASDN), located at the end of the renal BY ALDOSTERONE AND WITH-NO- crease PNa/PCl in the TALH and thereby tubule, encompasses the distal convo- LYSINE KINASES allow generation of the NaCl dilution luted tubule, connecting tubule, and potential. In this model, claudin-16 and collecting duct. In these segments, urine The major function of aldosterone is to -19 regulate Ca2+ and Mg2+ transport in- composition is fine-tuned by active re- stimulate renal salt reabsorption, which directly, by affecting the electrical driving absorption of Na+ and secretion of K+ is largely mediated by stimulation of force. and H+ against steep uphill transtubular ASDN transcellular transport. However, gradients that can reach lumen to blood mineralocorticoids can also regulate para- ratios of 1:3 (Na+), 20:1 (K+), and 1000:1 cellular permeability. For example, min- REGULATION OF TAL CLAUDINS (H+). Thus, a major role of the paracel- eralocorticoids reduce Na permeability in BY EXTRACELLULAR CALCIUM lular pathway is to act as a cation barrier the inner medullary collecting duct.92–94 to prevent backleak of actively transpor- Weinstein has estimated that up to two The Ca-sensing receptor (CaSR) plays a ted cations (Figure 3C). In addition, the thirds of Na+ reabsorbed transcellularly major role in regulating whole-body Ca2+ cortical collecting duct paracellular in the cortical collecting duct may back- 2 homeostasis. In the kidney, it is primarily pathway is permeable to Cl ,84 presum- flux via paracellular pathways.95 Thus, al- expressed on the basolateral membrane of ably providing the counterion to accom- dosterone may play a significant role in the TALH, where it reduces renal tubular pany electrogenic Na+ transport via the limiting paracellular backleak of Na+ Ca2+ reabsorption and induces calciuresis epithelial Na+ channel, ENaC. along the collecting duct and thereby en- in response to a Ca load.78,79 Although The ASDNexpresses claudin-3, -4, -7, -8, hance net Na+ reabsorption. However, the activation of the TALH CaSR may inhibit and -10. The function of claudin-7 is molecular mechanism for this effect is not NKCC2 expression79 or activity and cause unsettled.When overexpressedinLLC-PK known. Le Moellic et al. reported another 2 calciuresis by a loop diuretic–like effect, cells, it appeared to reduce Cl permeabil- role for aldosterone: to increase paracellu- 2 recent evidence suggests that the main ac- ity and act as a Cl barrier.85 However, lar anion permeability in a rat cortical tion of CaSR in the tubule is to regulate knockdown of its expression paradoxi- collecting duct cell line.96 This correlated 2 paracellular permeability. Loupy et al. cally also decreased Cl permeability, sug- temporally with phosphorylation of showed that a CaSR antagonist increased gesting that claudin-7 might normally claudin-4 at a threonine residue, although a 2 Ca2+ permeability in isolated perfused behave as a Cl pore and be responsible causal relationship was not established. 2 TALH, with no change in transepithelial for the paracellular Cl conductance in With-no-lysine(WNK)1andWNK4are voltage or Na flux.80 This appears to be the ASDN.45 Mice with constitutive protein kinases that play key roles in switch- mediated by regulation of the expres- knockout of claudin-7 die in neonatal life ing the ASDN between salt reabsorption and sion of claudin-14. Activation of the of renal salt wasting, dehydration, and re- K secretion and are mutated in pseudohy- CaSR causes robust upregulation of nal failure, consistent with a role for poaldosteronism, type II.97 In addition to 2 claudin-14,81,82 which, through physical claudin-7 in ASDN Cl reabsorption.86 regulating transcellular transport proteins, interaction, inhibits paracellular cation Claudin-4 and -8 act as cation barriers WNK4, which is localized to the tight junc- channels formed by claudin-16 and when overexpressed MDCK cells.87–89 tion in vivo,97 may also regulate paracellular 2 -19.81 The signaling mechanism seems However, knockdown experiments in Cl permeability. When overexpressed in to involve CaSR somehow inhibiting M1 and IMCD3 cell lines suggest that in cell lines, WNK4 (particularly the pseudo- calcineurin, a phosphatase that nor- native collecting ducts they are more likely hypoaldosteronism, type II mutant) stimu- 2 2 mally activates NFAT to increase tran- to function primarily as Cl pores.90 Fur- lates paracellular Cl conductance.98–100 scription of two micro-RNAs (miR-9 thermore, claudin-4 and -8 seem to inter- The exact mechanism is unclear. There is and miR-374), thereby downregulating actwitheachother,andclaudin-8is evidence both for,98,100 and against,101 direct claudin-14 expression.81,83 The central required for claudin-4 to assemble into phosphorylation by WNK4 of several clau- role of claudin-14 is supported by the tight junction strands.90 This suggests a din isoforms, including claudin-4 and -7. striking observation that claudin-14 potential role for claudin-4 and -8 in knockout mice are unable to increase ASDN salt reabsorption. Interestingly, their fractional excretion of calcium in claudin-4 null mice have no abnormality CLAUDINS IN HUMAN KIDNEY response to a high-Ca2+ diet81 and ex- in serum electrolytes at 3 months of age DISEASES hibit complete loss of regulation of uri- and exhibit a small increase in fractional 2 nary Ca2+ excretion in response to a excretion of Cl but not of Na+.91 Unex- The first inherited disorder of claudins to CaSR agonist or antagonist.83 pectedly, these mice are also hypercalciuric, be identified was FHHNC.70 This

J Am Soc Nephrol 26: 11–19, 2015 Claudins and the Kidney 15 BRIEF REVIEW www.jasn.org autosomal recessive disease is character- port function, and potentially in glomer- Blasig IE: Formation of tight junction: De- 2+ terminants of homophilic interaction be- ized by renal Mg wasting, hypercalciuria, ular epithelial cell function, they will – 102 tween classic claudins. FASEB J 22: 146 and nephrocalcinosis. Patients with probably be found to be involved in many 158, 2008 FHHNC are usually treated with oral different disease processes within the 11. Piehl C, Piontek J, Cording J, Wolburg H, 2+ 2+ Mg supplements, but their serum Mg kidney. Blasig IE: Participation of the second extra- levels remain very low.102,103 The hyper- cellular loop of claudin-5 in paracellular tightening against ions, small and large calciuria can be ameliorated with thiazide – 104 molecules. Cell Mol Life Sci 67: 2131 2140, therapy but generally cannot be com- 2010 103 ACKNOWLEDGMENTS pletely corrected. Despite treatment, 12. Van Itallie CM, Colegio OR, Anderson JM: CKD occurs in childhood and adoles- The cytoplasmic tails of claudins can in- cence, and progression to ESRD is typical. Work by the author cited in this manuscript fluence tight junction barrier properties was supported by National Institutes of through effects on protein stability. J Cadaveric renal transplantation normalizes – 2+ Health grants R01-DK062283 and U01- Membr Biol 199: 29 38, 2004 the serum Mg concentration and urinary 13. González-Mariscal L, Garay E, Quirós M: 2+ fi Ca excretion, con rming that the un- GM094627. Regulation of claudins by post-translational derlying defect is renal in origin.103 Classic modifications and cell signaling cascades. FHHNC is due to mutations in claudin-16. In: Claudins, edited by Yu AS, Philadelphia, – Mutations in claudin-19 cause FHHNC DISCLOSURES PA, Elsevier, 2010, pp 113 150 14. Van Itallie CM, Gambling TM, Carson JL, None. that is associated with ocular abnormal- Anderson JM: Palmitoylation of claudins is ities, including macular colobomata, required for efficient tight-junction local- 71 – nystagmus, and myopia. Claudin-19 is REFERENCES ization. JCellSci118: 1427 1436, 2005 normally expressed at high levels in the 15. Itoh M, Furuse M, Morita K, Kubota K, retina,71 but why mutations in this pro- Saitou M, Tsukita S: Direct binding of three 1. Frömter E, Diamond J: Route of passive ion tight junction-associated MAGUKs, ZO-1, tein cause these ocular disorders is un- permeation in epithelia. Nat New Biol 235: ZO-2, and ZO-3, with the COOH termini of known. 9–13, 1972 claudins. JCellBiol147: 1351–1363, 1999 Claudin-14 has now been implicated 2. Farquhar MG, Palade GE: Junctional com- 16. Hamazaki Y, Itoh M, Sasaki H, Furuse M, in the pathogenesis of hypercalciuria and plexes in various epithelia. 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