Fig. 1.

Model of how apical Na⁺/H⁺ exchange mediates NaCl absorption (left) and luminal acidification (right). The electrochemical driving force (Δμ) is the low cell [Na⁺] and negative interior voltage generated by the Na⁺/K⁺-ATPase. The apical Na⁺/H⁺ exchanger NHE3 is highlighted in gray. Coupling of Na⁺/H⁺ exchange with Cl⁻/base (B⁻) exchange and acid (HB) recycling or triple coupling of Na⁺-sulfate cotransport, sulfate–anion (X⁻) exchange and Cl⁻/anion exchange constitutes net apical NaCl entry. The Na⁺ that enters with organic solutes (Org) also results in net NaCl entry when coupled to paracellular Cl⁻ transport. Basolateral transcellular Cl⁻ exit is achieved via diverse mechanisms (Cl⁻ channel, Na⁺-dependent Cl⁻HCO₃⁻ exchange, and KCl cotransport). Luminal acidification by NHE3 titrates filtered HCO₃⁻ which results in HCO₃⁻ absorption. As luminal [HCO₃⁻] falls with isotonic fluid absorption, luminal Cl⁻ is concentrated (graph in middle panel) along the length of the proximal tubule, which enhances the Δμ for paracellular Cl⁻ diffusion (TF–P, tubular fluid to plasma concentration ratio). The H⁺ extruded by NHE3 also titrate filtered trivalent citrate to bivalent citrate, which is taken up by the Na⁺-citrate cotransporter. Citrate reabsorption is tantamount to base equivalent absorption. The metabolism of neutral glutamine (Gln) generates NH₄⁺ (acid) and HCO₃⁻ (base). NH₄⁺ secretion is mediated by NHE3 either by luminal trapping of diffused NH₃ or by NH₄⁺ traversing as a substrate. Base exit is mediated by the Na⁺-HCO₃⁻ cotransporter