Essential role of NHE3 in facilitating formate-dependent NaCL absorption in the proximal tubule

The absorption of NaCl in the proximal tubule is markedly stimulated by formate. This stimulation of NaCl transport is consistent with a cell model involving Cl^--formate exchange in parallel with pH-coupled formate recycling due to nonionic diffusion of formic acid or H⁺-formate cotransport. The formate recycling process requires H⁺ secretion. Although Na⁺-H⁺ exchanger isoform NHE3 accounts for the largest component of H⁺ secretion in the proximal tubule, 40-50% of the rates of HCO₃^- absorption or cellular H⁺ extrusion persist in NHE3 null mice. The purpose of the present investigation is to use NHE3 null mice to directly test the role of apical membrane NHE3 in mediating NaCl absorption stimulated by formate. We demonstrate that formate stimulates NaCl absorption in the mouse proximal tubule microperfused in vivo, but the component of NaCl absorption stimulated by formate is absent in NHE3 null mice. In contrast, stimulation of NaCl absorption by oxalate is preserved in NHE3 null mice, indicating that oxalate-stimulated NaCl absorption is independent of Na⁺-H⁺ exchange. The virtually complete dependence of formate-induced NaCl absorption on NHE3 activity raises the possibility that NHE3 and the formate transporters are functionally coupled in the brush border membrane.