{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T01:32:51Z","timestamp":1792114371213,"version":"4.4.0"},"reference-count":39,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2020,1,7]],"date-time":"2020-01-07T00:00:00Z","timestamp":1578355200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["25282024"],"award-info":[{"award-number":["25282024"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["17K00860"],"award-info":[{"award-number":["17K00860"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009666","name":"Salt Science Research Foundation","doi-asserted-by":"publisher","award":["1831"],"award-info":[{"award-number":["1831"]}],"id":[{"id":"10.13039\/100009666","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Many nutrients are absorbed via Na+ cotransport systems, and therefore it is predicted that nutrient absorption mechanisms require a large amount of luminal Na+. It is thought that Na+ diffuses back into the lumen via paracellular pathways to support Na+ cotransport absorption. However, direct experimental evidence in support of this mechanism has not been shown. To elucidate this, we took advantage of claudin-15 deficient (cldn15\u2212\/\u2212) mice, which have been shown to have decreased paracellular Na+ permeability. We measured glucose-induced currents (\u0394Isc) under open- and short-circuit conditions and simultaneously measured changes in unidirectional 22Na+ fluxes (\u0394JNa) in Ussing chambers. Under short-circuit conditions, application of glucose resulted in an increase in \u0394Isc and unidirectional mucosal to serosal 22Na+ (\u2206JNaMS) flux in both wild-type and cldn15\u2212\/\u2212 mice. However, under open-circuit conditions, \u0394Isc was observed but \u2206JNaMS was strongly inhibited in wild-type but not in cldn15\u2212\/\u2212 mice. In addition, in the duodenum of mice treated with cholera toxin, paracellular Na+ conductance was decreased and glucose-induced \u2206JNaMS increment was observed under open-circuit conditions. We concluded that the Na+ which is absorbed by Na+-dependent glucose cotransport is recycled back into the lumen via paracellular Na+ conductance through claudin-15, which is driven by Na+ cotransport induced luminal negativity.<\/jats:p>","DOI":"10.3390\/ijms21020376","type":"journal-article","created":{"date-parts":[[2020,1,8]],"date-time":"2020-01-08T03:59:57Z","timestamp":1578455997000},"page":"376","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Na+-Coupled Nutrient Cotransport Induced Luminal Negative Potential and Claudin-15 Play an Important Role in Paracellular Na+ Recycling in Mouse Small Intestine"],"prefix":"10.3390","volume":"21","author":[{"given":"Michiko","family":"Nakayama","sequence":"first","affiliation":[{"name":"Laboratory of Physiology, School of Food and Nutritional Sciences, University of Shizuoka, Yada 52-1, Suruga-ku, Shizuoka 422-8526, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1816-1825","authenticated-orcid":false,"given":"Noriko","family":"Ishizuka","sequence":"additional","affiliation":[{"name":"Laboratory of Physiology, School of Food and Nutritional Sciences, University of Shizuoka, Yada 52-1, Suruga-ku, Shizuoka 422-8526, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3991-3689","authenticated-orcid":false,"given":"Wendy","family":"Hempstock","sequence":"additional","affiliation":[{"name":"Laboratory of Physiology, School of Food and Nutritional Sciences, University of Shizuoka, Yada 52-1, Suruga-ku, Shizuoka 422-8526, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2696-0897","authenticated-orcid":false,"given":"Akira","family":"Ikari","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, Gifu 501-1196, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3615-4602","authenticated-orcid":false,"given":"Hisayoshi","family":"Hayashi","sequence":"additional","affiliation":[{"name":"Laboratory of Physiology, School of Food and Nutritional Sciences, University of Shizuoka, Yada 52-1, Suruga-ku, Shizuoka 422-8526, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,1,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1146\/annurev-physiol-012110-142244","article-title":"Regulation of Electroneutral NaCl Absorption by the Small Intestine","volume":"73","author":"Kato","year":"2011","journal-title":"Annu. Rev. Physiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2223","DOI":"10.1073\/pnas.81.7.2223","article-title":"Conformational changes in the intestinal brush border sodium-glucose cotransporter labeled with fluorescein isothiocyanate","volume":"81","author":"Peerce","year":"1984","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"7501","DOI":"10.1074\/jbc.273.13.7501","article-title":"Cloning of a cDNA encoding the human sodium-dependent vitamin transporter mediating the uptake of pantothenate, biotin and lipoate","volume":"273","author":"Prasad","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"109","DOI":"10.3109\/09687689409162228","article-title":"Poly(a)+ RNA from the mucosa of rat jejunum induces novel na+-dependent and na+-independent leucine transport activities in in oocytes of xenopus laevis","volume":"11","author":"Yao","year":"1994","journal-title":"Mol. Membr. Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1093\/ajcn.81.2.341","article-title":"Origins and evolution of the Western diet: Health implications for the 21st century","volume":"81","author":"Cordain","year":"2005","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1038\/330379a0","article-title":"Expression cloning and cDNA sequencing of the Na+\/glucose co-transporter","volume":"330","author":"Hediger","year":"1987","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1007\/s002329900347","article-title":"Relationships between Na+\/glucose cotransporter (SGLT1) currents and fluxes","volume":"162","author":"Mackenzie","year":"1998","journal-title":"J. Membr. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1016\/S0016-5085(19)33288-3","article-title":"Diarrhea: A current view of the pathophysiology","volume":"63","author":"Phillips","year":"1972","journal-title":"Gastroenterology"},{"key":"ref_9","first-page":"G275","article-title":"Barrier function of epithelia","volume":"241","author":"Powell","year":"1981","journal-title":"Am. J. Physiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.tibs.2018.09.008","article-title":"The Claudins: From Tight Junctions to Biological Systems","volume":"44","author":"Tsukita","year":"2019","journal-title":"Trends Biochem. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1053\/gast.2001.21736","article-title":"Heterogeneity in expression and subcellular localization of claudins 2, 3, 4, and 5 in the rat liver, pancreas, and gut","volume":"120","author":"Rahner","year":"2001","journal-title":"Gastroenterology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1007\/s12029-009-9110-y","article-title":"Distribution and Expression Pattern of Claudins 6, 7, and 9 in Diffuse- and Intestinal-Type Gastric Adenocarcinomas","volume":"41","author":"Teresa","year":"2010","journal-title":"J. Gastrointest. Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1053\/j.gastro.2007.11.040","article-title":"Megaintestine in Claudin-15-Deficient Mice","volume":"134","author":"Tamura","year":"2008","journal-title":"Gastroenterology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1053\/j.gastro.2010.08.006","article-title":"Loss of claudin-15, but not claudin-2, causes Na+ deficiency and glucose malabsorption in mouse small intestine","volume":"140","author":"Tamura","year":"2011","journal-title":"Gastroenterology"},{"key":"ref_15","first-page":"209","article-title":"Paracellular recirculation of sodium is essential to support nutrient absorption in the gastrointestinal tract: An hypothesis","volume":"9","author":"Halperin","year":"1986","journal-title":"Clin. Investig. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1007\/s11894-014-0376-2","article-title":"Oral rehydration therapy in the second decade of the twenty-first century","volume":"16","author":"Binder","year":"2014","journal-title":"Curr. Gastroenterol. Rep."},{"key":"ref_17","first-page":"G776","article-title":"Intestinal NaCl transport in NHE2 and NHE3 knockout mice","volume":"282","author":"Gawenis","year":"2002","journal-title":"Am. J. Physiol. Liver Physiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1007\/BF02209145","article-title":"Contribution of solvent drag through intercellular junctions to absorption of nutrients by the small intestine of the rat","volume":"100","author":"Pappenheimer","year":"1987","journal-title":"J. Membr. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1053\/j.gastro.2010.10.042","article-title":"d-glucose acts via sodium\/glucose cotransporter 1 to increase NHE3 in mouse jejunal brush border by a Na+\/H+ exchange regulatory factor 2dependent process","volume":"140","author":"Lin","year":"2011","journal-title":"Gastroenterology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1007\/s004240050704","article-title":"S3226, a novel inhibitor of Na+\/H+ exchanger subtype 3 in various cell types","volume":"436","author":"Schwark","year":"1998","journal-title":"Pflugers Arch. Eur. J. Physiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"C26","DOI":"10.1152\/ajpcell.1984.247.1.C26","article-title":"Control of potassium transport by turtle colon: Role of membrane potential","volume":"247","author":"Halm","year":"1984","journal-title":"Am. J. Physiol."},{"key":"ref_22","first-page":"G799","article-title":"Luminal Na+ homeostasis has an important role in intestinal peptide absorption in vivo","volume":"315","author":"Ishizuka","year":"2018","journal-title":"Am. J. Physiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1085\/jgp.59.3.318","article-title":"Ionic Conductances of Extracellular Shunt Pathway in Rabbit Ileum","volume":"59","author":"Frizzell","year":"1972","journal-title":"J. Gen. Physiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1172\/JCI200318326","article-title":"Intestinal ion transport and the pathophysiology of diarrhea Find the latest version: Intestinal ion transport and the pathophysiology of diarrhea","volume":"111","author":"Field","year":"2003","journal-title":"J. Clin. Investig."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1436","DOI":"10.1152\/ajplegacy.1974.227.6.1436","article-title":"Intestinal conductance and permselectivity changes with theophylline and choleragen","volume":"227","author":"Powell","year":"1974","journal-title":"Am. J. Physiol."},{"key":"ref_26","first-page":"G1015","article-title":"Lateral intercellular space volume as a determinant of CFTR-mediated anion secretion across small intestinal mucosa","volume":"286","author":"Gawenis","year":"2004","journal-title":"Am. J. Physiol. Liver Physiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/j.mam.2012.11.003","article-title":"Proton-coupled oligopeptide transporter family SLC15: Physiological, pharmacological and pathological implications","volume":"34","author":"Smith","year":"2013","journal-title":"Mol. Aspects Med."},{"key":"ref_28","first-page":"297","article-title":"The Mode of Action of NHE3 Inhibitors in Intestinal Na + Absorption","volume":"4","author":"Ishizuka","year":"2019","journal-title":"Gastroenterol. Med. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"10105","DOI":"10.3390\/ijms160510105","article-title":"Effect of \u03b3-cyclodextrin inclusion complex on the absorption of R-\u03b1-lipoic acid in rats","volume":"16","author":"Uchida","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"187","DOI":"10.2337\/db11-1029","article-title":"Na+-d-glucose cotransporter SGLT1 is pivotal for intestinal glucose absorption and glucose-dependent incretin secretion","volume":"61","author":"Gorboulev","year":"2012","journal-title":"Diabetes"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1085\/jgp.200810154","article-title":"Molecular Basis for Cation Selectivity in Claudin-2\u2013based Paracellular Pores: Identification of an Electrostatic Interaction Site","volume":"133","author":"Yu","year":"2009","journal-title":"J. Gen. Physiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1053\/j.gastro.2012.10.035","article-title":"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","volume":"144","author":"Wada","year":"2013","journal-title":"Gastroenterology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1038\/969","article-title":"Renal and intestinal absorptive defects in mice lacking the NHE3 Na+\/H+ exchanger","volume":"19","author":"Schultheis","year":"1998","journal-title":"Nat. Genet."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"37962","DOI":"10.1074\/jbc.M607527200","article-title":"slc26a3 (dra)-deficient mice display chloride-losing diarrhea, enhanced colonic proliferation, and distinct up-regulation of ion transporters in the colon","volume":"281","author":"Schweinfest","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1038\/294451a0","article-title":"Regulation of epithelial tight junction permeability by cyclic AMP","volume":"294","author":"Duffey","year":"1981","journal-title":"Nature"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1172\/JCI106874","article-title":"Effect of cholera enterotoxin on Ion transport across isolated ileal mucosa","volume":"51","author":"Field","year":"1972","journal-title":"J. Clin. Investig."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2628","DOI":"10.1001\/jama.291.21.2628","article-title":"Scientific Rationale for a Change in the Composition of Oral Rehydration Solution","volume":"291","author":"Duggan","year":"2004","journal-title":"JAMA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1038\/ki.2008.184","article-title":"Fructose-induced hypertension: Essential role of chloride and fructose absorbing transporters PAT1 and Glut5","volume":"74","author":"Singh","year":"2008","journal-title":"Kidney Int."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1016\/0140-6736(92)90079-I","article-title":"Hypernatraemia surveillance during a national diarrhoeal diseases control project in Egypt","volume":"339","author":"Fayad","year":"1992","journal-title":"Lancet"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/2\/376\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T14:04:12Z","timestamp":1760364252000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/2\/376"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,7]]},"references-count":39,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2020,1]]}},"alternative-id":["ijms21020376"],"URL":"https:\/\/doi.org\/10.3390\/ijms21020376","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.737217171.793570318","asserted-by":"object"}]},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,1,7]]}}}