Regulated expression of claudin-4 decreases paracellular conductance through a selective decrease in sodium permeability

Itallie, Christina Van; Rahner, Christoph; Anderson, James M.

doi:10.1172/jci12464

Cited by 546 publications

(509 citation statements)

References 36 publications

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“…Its presence at the TJ decreases sodium ion permeability across paracellular space. 52 The present findings show selective dissociation of claudin-4 from TJ in response to ameba-derived PGE 2 or a high dose of purified PGE 2 . We note that crosstalk occurs between PGE 2 -induced activation of apical chloride channels (CFTR) and alteration at the TJ.…”

Section: Discussionsupporting

confidence: 55%

Prostaglandin E2 Produced by Entamoeba histolytica Signals via EP4 Receptor and Alters Claudin-4 to Increase Ion Permeability of Tight Junctions

Lejeune

Chadee

2011

The American Journal of Pathology

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Entamoeba histolytica is a protozoan parasite that causes amebic dysentery characterized by severe watery diarrhea. Unfortunately, the parasitic factors involved in the pathogenesis of diarrhea are poorly defined. Prostaglandin E 2 (PGE 2 ) is a host lipid mediator associated with diarrheal diseases. Intriguingly, E. histolytica produces and secretes this inflammatory molecule. We investigated the mechanism whereby ameba-derived PGE 2 induces the onset of diarrhea by altering ion permeability of paracellular tight junctions (TJs) in colonic epithelia. PGE 2 decreased barrier integrity of TJs in a dose-and timedependent manner, as measured by transepithelial resistance. PGE 2 signals were selectively transduced via the EP4 receptor. Furthermore, PGE 2 signaling decreased TJ integrity, as revealed by EP receptorspecific agonist and antagonist studies. Loss of mucosal barrier integrity corresponded with increased ion permeability across TJs. Subcellular fractionation and confocal microscopy studies highlighted a significant spatial alteration of an important TJ protein, claudin-4, that corresponded with increased sodium ion permeability through TJs toward the lumen. Moreover, PGE 2 -induced luminal chloride secretion was a prerequisite for alterations at TJs. Thus, the gradient of NaCl created across epithelia could serve as a trigger for osmotic water flow that leads to diarrhea. Our results highlight a pathological role for E. histolyticaderived PGE 2 in the onset of diarrhea.

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Section: Discussionsupporting

confidence: 55%

Prostaglandin E2 Produced by Entamoeba histolytica Signals via EP4 Receptor and Alters Claudin-4 to Increase Ion Permeability of Tight Junctions

Lejeune

Chadee

2011

The American Journal of Pathology

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“…For example, in Madin Darby Canine Kidney cells, overexpression of claudin-4 increased transepithelial electrical resistance and increased chloride selectivity of the paracellular pathway. 5 Also, claudin-4 knockdown in primary rat alveolar type 2 cells and human distal lung epithelial cells resulted in a significant decrease in transepithelial electrical resistance. 16 As one of the most abundant claudins in the alveolar epithelium, 15 differences in claudin-4 expression are likely to influence paracellular permeability.…”

Section: Discussionmentioning

confidence: 98%

“…Although Intact tight junctions are required for AFC, differential expression of transmembrane tight junction proteins modulates epithelial paracellular permeability to ions and other solutes. [5][6][7][8][9][10][11] Foremost among these tight junction proteins is the claudin family. [12][13][14] In both types 1 and 2 pneumocytes, claudin-4 is expressed at high levels.…”

mentioning

confidence: 99%

“…16 Claudin-4 is of particular interest because it confers low-ion conductance and relative chloride selectivity to the paracellular pathway in Madin-Darby Canine Kidney cells. 5 Concomitant transport of chloride is necessary to minimize the energy requirement for sodium transport, and a third of chloride transport in the alveolar epithelium occurs via the paracellular pathway. 1,17 Therefore, changes in paracellular sodium and chloride transport would be expected to directly impact alveolar fluid clearance.…”

mentioning

confidence: 99%

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Claudin-4 Levels Are Associated with Intact Alveolar Fluid Clearance in Human Lungs

Rokkam

LaFemina

Lee

et al. 2011

The American Journal of Pathology

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“…It creates a charge-selective pore in the paracellular pathway across the epithelia and selectively restricts passage of sodium in the paracellular space. 27 Significant increase of claudin-4 has been detected in pancreatic, 22,28 prostate, 20 cervical 26 and ovarian cancers. 29 For the first time, our study detected high expression of claudin-4 in biliary tract cancers in contrast to hepatocellular carcinomas at both RNA and protein levels.…”

Section: Discussionmentioning

confidence: 99%

Claudin-4 differentiates biliary tract cancers from hepatocellular carcinomas

et al. 2006

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The recently identified claudins are dominant components of tight junctions, responsible for cell adhesion, polarity and paracellular permeability. Certain claudins have been shown to have relevance in tumor development, with some of them, especially claudin-4, even suggested as future therapeutic target. The aim of the present study was to analyze the expression of claudin-4 in the biliary tree, biliary tract cancers and hepatocellular carcinomas. A total of 107 cases were studied: 53 biliary tract cancers, 50 hepatocellular carcinomas, 10 normal liver and 10 normal extrahepatic biliary duct samples. Immunohistochemical analysis was performed on conventional specimens and on tissue microarrays as well. Claudin-4 was further investigated by Western blot analysis and real-time RT-PCR. Intense membranous immunolabeling was found for claudin-4 in all biliary tract cancers unrelated to the primary site of origin, namely intrahepatic, extrahepatic or gallbladder cancers. Normal biliary epithelium showed weak positivity for claudin-4. In contrast, normal hepatocytes and tumor cells of hepatocellular carcinomas did not express claudin-4. The results of Western immunoblot analysis and real-time RT-PCR were in correlation with the immunohistochemical findings. Cytokeratins, as CK7 (92%) and CK19 (83%) were mostly positive in biliary tract cancers, however, one-third of hepatocellular carcinomas also expressed CK7 (34%). HSA antibody (HepPar1) reacted with the majority of hepatocellular carcinomas (86%), while being positive in a low percentage of the biliary tract cancers (8%). In conclusion, this is the first report of a significantly increased claudin-4 expression in biliary tract cancers, which represents a novel feature of tumors of biliary tract origin. Claudin-4 expression seems to be a useful marker in differentiating biliary tract cancers from hepatocellular carcinomas and could well become a potential diagnostic tool.

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Regulated expression of claudin-4 decreases paracellular conductance through a selective decrease in sodium permeability

Cited by 546 publications

References 36 publications

Prostaglandin E2 Produced by Entamoeba histolytica Signals via EP4 Receptor and Alters Claudin-4 to Increase Ion Permeability of Tight Junctions

Prostaglandin E2 Produced by Entamoeba histolytica Signals via EP4 Receptor and Alters Claudin-4 to Increase Ion Permeability of Tight Junctions

Claudin-4 Levels Are Associated with Intact Alveolar Fluid Clearance in Human Lungs

Claudin-4 differentiates biliary tract cancers from hepatocellular carcinomas

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