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

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

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