Role of SLC26-Mediated Cl− /Base Exchange in Proximal Tubule NaCl Transport

Abstract

The majority of the Na+ and Cl- filtered by the kidney is reabsorbed in the proximal tubule. In this nephron segment, a significant fraction of Cl- is transported via apical membrane Cl-/base exchange: Cl-/formate exchange in parallel with Na+/H+ exchange and H+/formate cotransport, and Cl-/oxalate exchange in parallel with oxalate/sulfate exchange and Na+/sulfate cotransport. Apical membrane Cl--OH- or Cl-/HCO3- exchange has also been observed. NHE3 mediates most if not all apical membrane Na+/H+ exchange in the proximal tubule. We evaluated SLC26 family members as candidates to mediate proximal tubule Cl-/base exchange. We could not detect pendrin (SLC26A4) expression in the proximal tubule, and found no change in transtubular NaCl absorption in pendrin null mice. We did find expression of SLC26A6 (CFEX, PAT1) on the apical membrane of proximal tubule cells, and demonstrated that SLC26A6 is capable of mediating the Cl-/base exchange activities described to take place across the brush border membrane. Microperfusion studies on SLC26A6 null mice demonstrated that SLC26A6 is essential for oxalate-dependent NaCl absorption but does not contribute to baseline transport, suggesting it primarily mediates Cl-/oxalate exchange rather than Cl--OH- or Cl-/HCO3- exchange in the proximal tubule. Expression of SLC26A7 was also detected on the brush border membrane of proximal tubule cells. Finally, we demonstrated an essential role for the scaffolding protein PDZK1 in apical membrane expression of SLC26A6.