Claudin-18 Loss Alters Transcellular Chloride Flux but not Tight Junction Ion Selectivity in Gastric Epithelial Cells
| Autor: | Mahnoor Baqai, James G. Fox, Susan J. Hagen, Nishita Sinha, Yue Li, Tyler J. Caron, Jerrold R. Turner, Sureshkumar Muthupalani, Lay-Hong Ang, Kathleen E Scott |
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| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine Cell Membrane Permeability Mice Cldn18-KO mice claudin-18 knockout mice that are mice deficient in both stomach and lung isoforms of claudin-18 Ussing Chambers 0302 clinical medicine Gastric glands Cldn claudin Claudin-2 RNA-Seq Transcellular ANOVA analysis of variance Original Research Epithelial polarity Mice Knockout Tight junction Chemistry Gastroenterology PD potential difference RNAseq Up-Regulation Cell biology FFPE formalin-fixed paraffin-embedded medicine.anatomical_structure MIT Massachusetts Institute of Technology NaK-ATPase sodium (Na+) potassium (K+)-ATPase stCldn18-KO mice claudin-18 knockout mice with the knockout directed specifically to the stomach isoform of claudin-18 Paracellular transport Models Animal Female 030211 gastroenterology & hepatology tissues digestive system Tight Junctions 03 medical and health sciences Chlorides medicine Animals TER transepithelial resistance lcsh:RC799-869 Claudin Ion transporter Ions SE standard error Hepatology urogenital system Epithelial Cells FD-4 fluorescein isothiocyanate-dextran average molecular weight 4000 Genomic Profile Paracellular Permeability Gastric Cancer 030104 developmental biology Gastric Mucosa Permeability (electromagnetism) NKCC1 sodium (Na+)-potassium (K+)-2 chloride (2 Cl-) cotransporter-1 Claudins lcsh:Diseases of the digestive system. Gastroenterology |
| Zdroj: | Elsevier Cellular and Molecular Gastroenterology and Hepatology, Vol 11, Iss 3, Pp 783-801 (2021) Cellular and Molecular Gastroenterology and Hepatology |
| ISSN: | 2352-345X |
| DOI: | 10.1016/j.jcmgh.2020.10.005 |
| Popis: | Background & Aims Tight junctions form a barrier to the paracellular passage of luminal antigens. Although most tight junction proteins reside within the apical tight junction complex, claudin-18 localizes mainly to the basolateral membrane where its contribution to paracellular ion transport is undefined. Claudin-18 loss in mice results in gastric neoplasia development and tumorigenesis that may or may not be due to tight junction dysfunction. The aim here was to investigate paracellular permeability defects in stomach mucosa from claudin-18 knockout (Cldn18-KO) mice. Methods Stomach tissue from wild-type, heterozygous, or Cldn18-KO mice were stripped of the external muscle layer and mounted in Ussing chambers. Transepithelial resistance, dextran 4 kDa flux, and potential difference (PD) were calculated from the chambered tissues after identifying differences in tissue histopathology that were used to normalize these measurements. Marker expression for claudins and ion transporters were investigated by transcriptomic and immunostaining analysis. Results No paracellular permeability defects were evident in stomach mucosa from Cldn18-KO mice. RNAseq identified changes in 4 claudins from Cldn18–KO mice, particularly the up-regulation of claudin-2. Although claudin-2 localized to tight junctions in cells at the base of gastric glands, its presence did not contribute overall to mucosal permeability. Stomach tissue from Cldn18–KO mice also had no PD versus a lumen-negative PD in tissues from wild-type mice. This difference resulted from changes in transcellular Cl– permeability with the down-regulation of Cl– loading and Cl– secreting anion transporters. Conclusions Our findings suggest that Cldn18-KO has no effect on tight junction permeability in the stomach from adult mice but rather affects anion permeability. The phenotype in these mice may thus be secondary to transcellular anion transporter expression/function in the absence of claudin-18. Graphical abstract |
| Databáze: | OpenAIRE |
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