Brief review
Role of claudins in renal calcium handling
Rol de las claudinas en el manejo renal del calcio
Armando Luis Negri
Departamento de Fisiología, Universidad del Salvador, Ciudad Autónoma de Buenos Aires, CABA, Argentina
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"https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2013251415000589?idApp=UINPBA000064" "url" => "/20132514/0000003500000004/v1_201511210014/S2013251415000589/v1_201511210014/en/main.assets" ] "en" => array:20 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Brief review</span>" "titulo" => "Role of claudins in renal calcium handling" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "347" "paginaFinal" => "352" ] ] "autores" => array:1 [ 0 => array:3 [ "autoresLista" => "Armando Luis Negri" "autores" => array:1 [ 0 => array:3 [ "nombre" => "Armando" "apellidos" => "Luis Negri" "email" => array:2 [ 0 => "armando.negri@gmail.com" 1 => "negri@casasco.com.ar" ] ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Departamento de Fisiología, Universidad del Salvador, Ciudad Autónoma de Buenos Aires, CABA, Argentina" "identificador" => "aff0005" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Rol de las claudinas en el manejo renal del calcio" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2063 "Ancho" => 1587 "Tamanyo" => 123362 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Epithelial cell lining the TAL: transcellular and paracellular transport.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Epithelial transport can occur by the transcellular route, across epithelial cells, or via a paracellular route between epithelial cells. In the last decade, evidence has accumulated supporting the fundamental role of paracellular channels in transepithelial flux of ions. The paracellular channel or route is found in the tight junctions (zonulae occludentes) of the epithelium in vertebrates. Tight junctions are the most apical structure of the intercellular junctional complex. Tight junctions are composed of a large number of different proteins. Of those, membrane proteins probably play a central role in determining paracellular permeability, as their extracellular domains protrude into the paracellular space, with an ideal position to influence paracellular movement of solutes. The cell membrane proteins of the tight junction include occludins, junctional adhesion molecules (JAM), and claudins. Claudins include a large family of at least 26 proteins that were first identified in 1998.<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">1</span></a> It was subsequently found that claudin-16, also known as paracellin-1, was mutated in familiar hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC).<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">FHHNC appeared to be due to a defect in paracellular reabsorption of calcium and magnesium in the thick ascending limb of the loop of Henle (TAL). This was a first indication that claudin-16, and by extension claudins in general, might play an important role in the paracellular ion permeability of the kidney. In a recent genomic association study, the gene for claudin-14 was identified as being associated with increased risk for development of hypercalciuric nephrolithiasis,<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">3</span></a> making this protein another candidate for involvement in reabsorption of bivalent cations. All this information led us to re-examine the significance of claudins present in the kidney and their regulation of tubular calcium reabsorption.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Claudin structure</span><p id="par0015" class="elsevierStylePara elsevierViewall">Claudins are 21 to 28<span class="elsevierStyleHsp" style=""></span>kDa proteins with 4 transmembrane domains, 2 extracellular loops, 2 cytoplasmic domains–one amino and one carboxyl terminal–and a short cytoplasmic loop. The first extracellular loop (ECL1) of claudins consists of approximately 50 amino acids with a common motif (GLWCC). It contains positively and negatively charged amino acids. The charges on ECL1 regulate ion selectivity by means of electrostatic effects. The second extracellular loop (ECL2) consists of approximately 25 amino acids with a predicted helix-loop-helix motif that mediates the intracellular interactions of claudins. The C-terminal domain contains the PDZ binding domain that is critical for interaction with the submembrane protein ZO-1 and the correct localisation of the claudin in the tight junction. In the renal epithelium, claudins have been shown to confer ion selectivity to the tight junction, resulting in differences in transepithelial resistance and paracellular permeability. For example, claudin-4, 5, 8, 11, and 14 selectively decrease tight junction permeability to cations, particularly to sodium, potassium, hydrogen, and ammonium, whereas claudin-2, 15, and 16 increase permeability to cations, particularly sodium, potassium, calcium, and magnesium.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">4</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Claudin expression in different tubular segments</span><p id="par0020" class="elsevierStylePara elsevierViewall">Most claudins are expressed in the renal tubule. Each segment and cell type expresses multiple isoforms. It is thought that the particular group of claudins expressed in each tubular segment determines the unique permeability properties of those segments.<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">5</span></a> Claudin-2 is highly expressed in the proximal tubule, mainly in the terminal part of the proximal tubule and the initial part of the thin descending loop of Henle; the fundamental role is to form paracellular cation-selective pores with high sodium conductivity. Claudin-10a and claudin-17 are both known to form anion-selective paracellular pores and are potential candidates for mediating paracellular reabsorption of chloride in the distal part of the this tubular segment. Claudins-16 and 19 are expressed in the thin and thick ascending limb of the loop of Henle and are clearly required for the paracellular reabsorption of bivalent cations. Some investigators think that these 2 claudins form the paracellular pore that mediates permeability to calcium and magnesium in the TAL. Others, such as Hou et al., have found that claudin-16 increases permeability to sodium, whereas claudin-19 reduces chlorine permeability, generating a dilution potential that drives paracellular calcium and magnesium movement. In the aldosterone-sensitive segment of the distal nephron, where active reabsorption of sodium and secretion of potassium and hydrogen ions take place, the main role of the paracellular pathway is to act as a cation barrier to prevent backleak of the actively-transported cations. In this segment, claudin-3, 4, 7, 8, and 10 are expressed. Claudins 4 and 8 act as cation barriers and interact in such a way that claudin-8 is required for claudin-4 to be assembled within the tight junction. Claudin-7 likely behaves as a Cl<span class="elsevierStyleSup">−</span> pore, being responsible for paracellular Cl<span class="elsevierStyleSup">−</span> conductivity in this tubule segment.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Renal calcium handling</span><p id="par0025" class="elsevierStylePara elsevierViewall">On average, the kidneys reabsorb 97–99% of the daily filtered load of calcium. Of this reabsorbed calcium, 60–65% is reabsorbed in the proximal tubule via the paracellular route and 25–30% is absorbed in the TAL, also paracellularly. The remaining 8% to 10% of filtered calcium is absorbed in the distal convoluted tubule, via the transcellular route.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">6</span></a> This transcellular transport consists of 3 stages: first, the apical entry of calcium via the TRPV5 (transient receptor protein-vanilloid 5) channel; second, the intracellular diffusion of calcium from the apical membrane to the basolateral membrane, bound to a protein called calbindin-D28K; and finally, the exit of calcium across the basolateral membrane by means of a Na/Ca exchanger (NCX1) and a calcium ATPase (PMCA1b).<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">7</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Proximal tubular reabsorption of calcium</span><p id="par0030" class="elsevierStylePara elsevierViewall">The proximal tubule of the adult kidney is a highly-permeable membrane that reabsorbs up to two thirds of the total filtered chloride load as well as two thirds of the ultrafiltrate volume. Almost half of all NaCl reabsorption is paracellular. The first portion of the proximal tubule reabsorbs bicarbonate-bound sodium preferentially over chloride-bound sodium, with associated reabsorption of water. This means the tubular fluid arriving at the final part of the S1 segment and the S2 and S3 segments of the proximal tubule has a higher chloride concentration than the peritubular liquid. In these sections of the proximal tubule, the paracellular route is preferentially permeable to chloride, which is reabsorbed by passive diffusion following the concentration gradient, in turn generating a lumen-positive potential, which drives paracellular sodium reabsorption. Claudin-2, which has been shown to act as a paracellular cationic pore,<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">8</span></a> is highly-expressed in the proximal tubule<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">9</span></a> and the thin descending limb of the loop of Henle, showing an axial increment in its levels of expression. Claudin-2 has been shown to be capable of transporting potassium and calcium, making it an excellent candidate for a paracellular pore that allows cation reabsorption. This was confirmed by Muto et al., using a knockout model for claudin-2 in mice.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">10</span></a> The mice had decreased cation permeability and a reduction in NaCl and water reabsorption when measured in isolated perfused proximal tubules. In balance studies in whole animals, the fractional excretions of sodium and chorine were comparable to those of wild mice in normal conditions. However, when they were given a high-salt diet, the excretions were significantly higher. These knockout mice did not have substantial changes in K metabolism but were hypercalciuric, suggesting that claudin-2 could mediate paracellular calcium reabsorption in the proximal tubule. In addition to claudin-2, the proximal tubule expresses claudins-10a, 12, and 17. Claudins-10a and 17 could function as anion-selective pores and be responsible for paracellular chlorine reabsorption. At an intestinal level, claudin-12 is regulated by vitamin D and functions as a calcium-selective pore. In the proximal tubule it could play a similar role, along with claudin-2.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Calcium reabsorption in the thick ascending limb of the loop of Henle</span><p id="par0035" class="elsevierStylePara elsevierViewall">The TAL is the most important renal tubular segment in terms of tubular calcium reabsorption. The epithelial cells that line the TAL form a barrier that is impermeable to water, with an active transcellular transport of sodium and chlorine, providing a paracellular route for selective reabsorption of calcium. Calcium is passively reabsorbed from the lumen to the interstitial space via the paracellular route, driven by a lumen-positive transepithelial voltage gradient<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">11</span></a> (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Generation of this transepithelial voltage is attributed to 2 mechanisms: 1) apical potassium secretion through the renal outer medullary potassium (ROMK) channel, and basolateral secretion of chlorine through chlorine Kb (ClC-Kb) and bartrin channels, driven by apical NaCl reabsorption via the Na2ClK cotransporter (NKCC2); and 2) the transepithelial diffusion voltage generated by the transepithelial concentration gradient of NaCl around the cation-selective paracellular channel in the TAL. In the first segment of the TAL, the first mechanism provides a voltage of around +8<span class="elsevierStyleHsp" style=""></span>mV, with minimal contribution from the diffusion potential in this early segment because the concentration gradient has not yet developed. With the continued reabsorption of NaCl along the axis of the TAL, the luminal fluid is diluted and a high concentration gradient is generated from the peritubular space to the tubular lumen of the distal segment of the TAL. As the paracellular permeability of the TAL is cation-selective, the positive transepithelial diffusion voltage is superimposed on the active transport transepithelial voltage, transforming into the main driving force for calcium reabsorption through the paracellular channel, with a voltage now substantially increased up to +30<span class="elsevierStyleHsp" style=""></span>mV.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Claudins in the paracellular channel of the thick ascending limb of the loop of Henle</span><p id="par0040" class="elsevierStylePara elsevierViewall">Several studies have led to a model in which claudins form paracellular channels,<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">12</span></a> in particular 2 of them: claudin-16, also known as paracellin-1, and claudin-19. Whilst claudin-16 is expressed only in the TAL of the kidney, claudin-19 has a broader expression, being found not only in the TAL of the kidney but also in the pigmented epithelium of the retina. Claudin-16 mediates paracellular cation permeability in the TAL.<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">13</span></a> Claudin-19 increases the cation selectivity of claudin-16, blocking anion permeability.<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">14</span></a> Paracellular cation selectivity is required to generate the lumen-positive transepithelial diffusion voltage that drives reabsorption of calcium and magnesium in the TAL.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">12</span></a> Patients with FHHNC have mutations in claudins-16 and 19. The phenotypic similarity of both mutations is explained by the direct interaction between the two proteins.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">15</span></a> However, claudin-19 mutations are invariably accompanied by severe ocular anomalies (including severe myopia, nystagmus, and macular coloboma), therefore this phenotype is known as FHHNC with severe ocular involvement.<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">16</span></a> Recently, a genome-wide association analysis study was performed on 37<span class="elsevierStyleHsp" style=""></span>734 patients with hypercalciuric lithiasis and 42<span class="elsevierStyleHsp" style=""></span>510 control participants without lithiasis, in Iceland and The Netherlands.<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">3</span></a> Four common synonymous variants at the locus of the claudin-14 gene (single nucleotide polymorphisms [SNP]) were significantly associated with renal lithiasis. Two of the variants were non-exonic and 2 were exonic. Both exonic SNPs were significantly associated with reduced bone mineral density. Urinary calcium excretion was higher in homozygous carriers of one of those polymorphisms than in non-carriers. Until recently, the localisation of claudin-14 at a renal level was disputed, until Gong et al. found that claudin-14 promoter activity was located exclusively in the TAL of mouse kidneys.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">17</span></a> In mice fed a normal diet, both claudin-14 mRNA and protein levels were extremely low. However, mice fed a high-calcium diet showed a marked increase in claudin-14 mRNA and protein levels in the TAL. In keeping with previous findings, claudin-14 works as a paracellular cation barrier. When co-expressed with claudin-16, claudin-14 inhibits the permeability of claudin-16, which is of great significance as a paracellular cation channel of the TAL. The knockout mice for claudin-14 had normal renal function under normal dietetic conditions. However, their kidneys excreted significantly less calcium and magnesium than wild mice when they were fed with a calcium-rich diet.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">17</span></a> The observed association between claudin-14 and nephrolithiasis could be explained by a dysregulation of claudin-14 that blocks the claudin-16 channel, producing a variable phenotype similar to that of FHHNC</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Integrated signalling system that controls calcium transport in the thick ascending limb of the loop of Henle</span><p id="par0045" class="elsevierStylePara elsevierViewall">As previously mentioned, the TAL is the main segment responsible for tubular reabsorption of calcium. The epithelial cells that make up the TAL form a barrier that is impermeable to water, actively transport NaCl via the transcellular route, and provide a paracellular channel for reabsorption of cations, including calcium. Paracellular calcium reabsorption is driven by a lumen-positive transepithelial voltage. There are 2 prerequisites for generation of this gradient: 1) a significant transepithelial NaCl gradient, dependent in the coordinated action of the Na/K/2Cl cotransporter (NKCC2) and the ROMK potassium channel, both in the apical membrane, and the chlorine channel (ClCKb-bartrin) in the basolateral membrane (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>); and 2) a cation-selective paracellular channel dependent on the interaction of claudin-16, 19, and 14. Monogenic diseases such as Bartter syndrome and FHHNC are caused by mutations in the genes underlying both of these prerequisites. The process of calcium reabsorption in the TAL is tightly regulated by the calcium-sensing receptor (CaSR), which monitors circulating calcium levels, adjusting the rate of renal excretion accordingly.<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">18</span></a> Recently, it was demonstrated that CaSR regulates calcium reabsorption by changing paracellular, not transcellular, permeability to calcium.<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">19</span></a> When CaSR is activated by a high dietary intake of calcium or by induction of hypercalcaemia due to prolonged calcitriol administration, claudin-14 expression in the TAL increases.<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">19</span></a> In keeping with this, CaSR activation by administration of the calcimimetic cinacalcet leads to a 40-fold increase in claudin-14 mRNA.<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">20</span></a> Furthermore, in 2 separate cell culture models, the overexpression of claudin-14 reduced paracellular calcium flux, thus reducing cationic permeability. Using animals that express Cre recombinase driven by the Six2 promoter, mice with undetectable levels of CaSR mRNA in the kidney were created.<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">21</span></a> These mice had urinary calcium levels lower than controls when they were challenged with a calcium-supplemented diet. This was associated with a significant reduction in claudin-14. Therefore, the activation of CaSR in the TAL increases claudin-14 expression, which in turn blocks paracellular calcium reabsorption.<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">20</span></a> Two micro-RNA that are directly regulated by CaSR in the cells of the TAL have also been identified: miR-9 and miR-374.<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">16</span></a> miR-9 and miR-374 recognise partially-complementary binding sites located at the 3′-UTR of claudin-14 RNA, suppressing their translation and inducing synergistic mRNA decay. Under normal dietary conditions, miR-9 and miR-374 repress the level of genetic expression of claudin-14 and protect the claudin-16 function in the paracellular channel. With a high calcium ingestion, CaSR is activated and down-regulates expression of miR9 and miR-374, causing a reciprocal increase in claudin-14 expression. The increase in claudin-14 proteins in the tight junctions inhibits the cation selectivity of claudin-16 in the paracellular channel, reducing calcium reabsorption in the TAL. Gong et al. recently reported that administration of histone deacetylase (HDAC) inhibitors reduced claudin-14 messenger RNA and drastically reduced urinary calcium excretion in mice.<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">22</span></a> Furthermore, treatment with HDAC inhibitors stimulates transcription of the genes coding for micro-RNA-9 and micro-RNA-374. These mRNAs that have been demonstrated to repress expression of claudin-14, the negative regulator of the paracellular pathway of calcium reabsorption (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Conclusion</span><p id="par0050" class="elsevierStylePara elsevierViewall">Claudins have been recognised as critical molecules in the regulation of paracellular calcium reabsorption at a renal level. In particular, claudin-14, 16, and 19 form paracellular channels in the TAL that regulate reabsorption of calcium and magnesium in this portion in the renal tubule. They are in turn regulated by the calcium-sensing receptor. The mutations and polymorphisms that affect the genes coding for these proteins appear to produce a dysregulation of urinary calcium excretion. This knowledge on the regulation of the paracellular pathway by CaSR using micro-RNA and its modification by HDCA inhibitors allows us to envisage new future treatments for hypercalciuric diseases.</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Conflicts of interest</span><p id="par0055" class="elsevierStylePara elsevierViewall">The author declares no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:14 [ 0 => array:3 [ "identificador" => "xres580856" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec597361" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres580857" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec597362" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Claudin structure" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Claudin expression in different tubular segments" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Renal calcium handling" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Proximal tubular reabsorption of calcium" ] 9 => array:3 [ "identificador" => "sec0030" "titulo" => "Calcium reabsorption in the thick ascending limb of the loop of Henle" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0035" "titulo" => "Claudins in the paracellular channel of the thick ascending limb of the loop of Henle" ] ] ] 10 => array:2 [ "identificador" => "sec0040" "titulo" => "Integrated signalling system that controls calcium transport in the thick ascending limb of the loop of Henle" ] 11 => array:2 [ "identificador" => "sec0045" "titulo" => "Conclusion" ] 12 => array:2 [ "identificador" => "sec0050" "titulo" => "Conflicts of interest" ] 13 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2014-10-27" "fechaAceptado" => "2015-02-20" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec597361" "palabras" => array:4 [ 0 => "Claudins" 1 => "Renal calcium reabsorption" 2 => "Calcium sensor receptor" 3 => "Paracellular pathway" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec597362" "palabras" => array:4 [ 0 => "Claudinas" 1 => "Reabsorción renal de calcio" 2 => "Receptor sensor de calcio" 3 => "Vía paracelular" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Paracellular channels occurring in tight junctions play a major role in transepithelial ionic flows. This pathway includes a high number of proteins, such as claudins. Within renal epithelium, claudins result in an ionic selectivity in tight junctions. Ascending thick limb of loop of Henle (ATLH) is the most important segment for calcium reabsorption in renal tubules. Its cells create a water-proof barrier, actively transport sodium and chlorine through a transcellular pathway, and provide a paracellular pathway for selective calcium reabsorption. Several studies have led to a model of paracellular channel consisting of various claudins, particularly claudin-16 and 19. Claudin-16 mediates cationic paracellular permeability in ATLH, whereas claudin-19 increases cationic selectivity of claudin-16 by blocking anionic permeability. Recent studies have shown that claudin-14 promoting activity is only located in ATLH. When co-expressed with claudin-16, claudin-14 inhibits the permeability of claudin-16 and reduces paracellular permeability to calcium. Calcium reabsorption process in ATLH is closely regulated by calcium sensor receptor (CaSR), which monitors circulating Ca levels and adjusts renal excretion rate accordingly. Two microRNA, miR-9 and miR-374, are directly regulated by CaSR. Thus, miR-9 and miR-374 suppress mRNA translation for claudin-14 and induce claudin-14 decline.</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Los canales paracelulares que se encuentran en las uniones estrechas tienen un papel fundamental en los flujos iónicos transepiteliales. Esta vía está formada por un gran número de proteínas, entre ellas, las claudinas. En el epitelio renal, las claudinas confieren selectividad iónica a la unión estrecha. La rama gruesa ascendente de Henle (RGAH) es el segmento tubular renal más importante en la reabsorción tubular de calcio. Sus células forman una barrera impermeable al agua, transportan activamente sodio y cloro por la vía transcelular y proveen una vía paracelular para la reabsorción selectiva de calcio. Varios estudios han llevado a un modelo en el que distintas claudinas forman el canal paracelular, especialmente la claudina 16 y 19. La claudina 16 media la permeabilidad paracelular catiónica en la RGAH mientras que la claudina 19 incrementa la selectividad catiónica de la claudina 16 bloqueando la permeabilidad aniónica. Recientemente se ha encontrado que la actividad promotora de la claudina 14 está localizada exclusivamente en la RAGH. Cuando se coexpresa con la claudina 16, la claudina 14 inhibe la permeabilidad de la claudina 16, reduciendo la permeabilidad paracelular al calcio. El proceso de reabsorción de calcio en la RGAH está estrechamente regulado por el receptor sensor de calcio (CaSR) que monitorea los niveles circulantes de Ca ajustando la tasa de excreción renal de forma acorde. Dos micro-ARN, los mir-9 y mir-374, son regulados directamente por el CaSR. Los miR-9 y miR-374 suprimen la traslación del ARNm de la claudina 14 e inducen su decaimiento.</p></span>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Luis Negri A. Rol de las claudinas en el manejo renal del calcio. Nefrologia. 2015;35:347–352.</p>" ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2063 "Ancho" => 1587 "Tamanyo" => 123362 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Epithelial cell lining the TAL: transcellular and paracellular transport.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1562 "Ancho" => 1565 "Tamanyo" => 107547 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Regulation of TAL claudins by extracellular calcium.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:22 [ 0 => array:3 [ "identificador" => "bib0115" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A single gene product claudin-1 or -2 reconstitutes tight junction strands and recruits occluding in fibroblasts" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "M. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 10 | 10 | 20 |
| 2024 October | 68 | 59 | 127 |
| 2024 September | 73 | 49 | 122 |
| 2024 August | 66 | 71 | 137 |
| 2024 July | 56 | 34 | 90 |
| 2024 June | 80 | 35 | 115 |
| 2024 May | 68 | 37 | 105 |
| 2024 April | 53 | 33 | 86 |
| 2024 March | 73 | 24 | 97 |
| 2024 February | 36 | 37 | 73 |
| 2024 January | 59 | 28 | 87 |
| 2023 December | 49 | 22 | 71 |
| 2023 November | 44 | 30 | 74 |
| 2023 October | 66 | 32 | 98 |
| 2023 September | 40 | 29 | 69 |
| 2023 August | 41 | 26 | 67 |
| 2023 July | 58 | 36 | 94 |
| 2023 June | 59 | 31 | 90 |
| 2023 May | 68 | 40 | 108 |
| 2023 April | 57 | 54 | 111 |
| 2023 March | 83 | 29 | 112 |
| 2023 February | 46 | 17 | 63 |
| 2023 January | 56 | 25 | 81 |
| 2022 December | 89 | 31 | 120 |
| 2022 November | 41 | 17 | 58 |
| 2022 October | 61 | 38 | 99 |
| 2022 September | 40 | 29 | 69 |
| 2022 August | 53 | 41 | 94 |
| 2022 July | 49 | 42 | 91 |
| 2022 June | 52 | 27 | 79 |
| 2022 May | 59 | 33 | 92 |
| 2022 April | 52 | 45 | 97 |
| 2022 March | 30 | 35 | 65 |
| 2022 February | 54 | 53 | 107 |
| 2022 January | 60 | 24 | 84 |
| 2021 December | 65 | 45 | 110 |
| 2021 November | 86 | 50 | 136 |
| 2021 October | 91 | 46 | 137 |
| 2021 September | 66 | 41 | 107 |
| 2021 August | 58 | 50 | 108 |
| 2021 July | 37 | 24 | 61 |
| 2021 June | 61 | 29 | 90 |
| 2021 May | 74 | 23 | 97 |
| 2021 April | 132 | 54 | 186 |
| 2021 March | 80 | 32 | 112 |
| 2021 February | 80 | 22 | 102 |
| 2021 January | 56 | 13 | 69 |
| 2020 December | 33 | 10 | 43 |
| 2020 November | 34 | 19 | 53 |
| 2020 October | 37 | 15 | 52 |
| 2020 September | 33 | 6 | 39 |
| 2020 August | 46 | 10 | 56 |
| 2020 July | 37 | 12 | 49 |
| 2020 June | 66 | 11 | 77 |
| 2020 May | 54 | 14 | 68 |
| 2020 April | 47 | 21 | 68 |
| 2020 March | 56 | 17 | 73 |
| 2020 February | 55 | 27 | 82 |
| 2020 January | 65 | 23 | 88 |
| 2019 December | 73 | 23 | 96 |
| 2019 November | 56 | 15 | 71 |
| 2019 October | 61 | 12 | 73 |
| 2019 September | 42 | 20 | 62 |
| 2019 August | 47 | 19 | 66 |
| 2019 July | 46 | 27 | 73 |
| 2019 June | 31 | 13 | 44 |
| 2019 May | 79 | 22 | 101 |
| 2019 April | 118 | 30 | 148 |
| 2019 March | 60 | 20 | 80 |
| 2019 February | 35 | 23 | 58 |
| 2019 January | 51 | 16 | 67 |
| 2018 December | 200 | 35 | 235 |
| 2018 November | 384 | 29 | 413 |
| 2018 October | 421 | 35 | 456 |
| 2018 September | 318 | 14 | 332 |
| 2018 August | 131 | 17 | 148 |
| 2018 July | 71 | 14 | 85 |
| 2018 June | 75 | 8 | 83 |
| 2018 May | 92 | 17 | 109 |
| 2018 April | 80 | 5 | 85 |
| 2018 March | 93 | 7 | 100 |
| 2018 February | 95 | 12 | 107 |
| 2018 January | 44 | 9 | 53 |
| 2017 December | 113 | 10 | 123 |
| 2017 November | 53 | 12 | 65 |
| 2017 October | 56 | 8 | 64 |
| 2017 September | 52 | 11 | 63 |
| 2017 August | 66 | 9 | 75 |
| 2017 July | 67 | 10 | 77 |
| 2017 June | 79 | 7 | 86 |
| 2017 May | 80 | 14 | 94 |
| 2017 April | 65 | 9 | 74 |
| 2017 March | 54 | 20 | 74 |
| 2017 February | 164 | 8 | 172 |
| 2017 January | 52 | 7 | 59 |
| 2016 December | 96 | 10 | 106 |
| 2016 November | 115 | 16 | 131 |
| 2016 October | 194 | 15 | 209 |
| 2016 September | 293 | 4 | 297 |
| 2016 August | 302 | 3 | 305 |
| 2016 July | 195 | 8 | 203 |
| 2016 June | 136 | 0 | 136 |
| 2016 May | 163 | 0 | 163 |
| 2016 April | 123 | 0 | 123 |
| 2016 March | 96 | 0 | 96 |
| 2016 February | 126 | 0 | 126 |
| 2016 January | 117 | 0 | 117 |
| 2015 December | 118 | 0 | 118 |
| 2015 November | 69 | 0 | 69 |
| 2015 October | 90 | 0 | 90 |
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