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 (22)Na(+) 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 (22)Na(+) (∆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.