Na⁺-Coupled Nutrient Cotransport Induced Luminal Negative Potential and Claudin-15 Play an Important Role in Paracellular Na⁺ Recycling in Mouse Small Intestine

• Main Authors: Michiko Nakayama, Noriko Ishizuka, Wendy Hempstock, Akira Ikari, Hisayoshi Hayashi
• Format: Article
• Language: English
• Published: MDPI AG 2020-01-01
• Series: International Journal of Molecular Sciences
• Subjects: tight junction; na⁺ cotransport; leaky epithelia
• Online Access: https://www.mdpi.com/1422-0067/21/2/376
• ISSN: 1422-0067

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 (<i>cldn15^{&#8722;/&#8722;}</i>) mice, which have been shown to have decreased paracellular Na⁺ permeability. We measured glucose-induced currents (&#916;<i>I</i>_sc) under open- and short-circuit conditions and simultaneously measured changes in unidirectional ²²Na⁺ fluxes (&#916;<i>J</i>^Na) in Ussing chambers. Under short-circuit conditions, application of glucose resulted in an increase in &#916;<i>I</i>_sc and unidirectional mucosal to serosal ²²Na⁺ (∆<i>J</i>^Na_MS) flux in both wild-type and <i>cldn15^{&#8722;/&#8722;}</i> mice. However, under open-circuit conditions, &#916;<i>I</i>_sc was observed but ∆<i>J</i>^Na_MS was strongly inhibited in wild-type but not in <i>cldn15^{&#8722;/&#8722;}</i> mice. In addition, in the duodenum of mice treated with cholera toxin, paracellular Na⁺ conductance was decreased and glucose-induced ∆<i>J</i>^Na_MS 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.