ClC-5 is a Cl^-/H⁺ antiporter localized to apical endosomes together with the vacuolar H⁺-ATPase (vH⁺-ATPase) and is expressed in proximal tubules (PT), thick ascending limbs, and A-type intercalated cells (A-IC) of collecting ducts (CD). Patients harbouring ClC-5 mutations develop Dent's disease, which is characterized by generalized PT dysfunction (low-molecular-weight proteinuria, hyperphosphaturia, and hypercalciuria). Some patients also show defective urinary acidification and modifications in the polarity and/or expression of vH⁺-ATPase in PT and A-IC for which the cause is still unknown. Our aim was to investigate the role of ClC-5 in the function of A-IC using Clcn5 knock-out (KO) mice.

Under baseline, Clcn5 KO mice exhibited hypercalciuria, higher titratable acid excretion and more acidic urine than controls (WT). After a chronic NH₄Cl-load, Clcn5 KO mice adequately increased their ammoniuria but could not further enhance their titratable acid excretion and showed a lower blood pH and bicarbonate with hyperchloremia and hyperkalemia compared to WT mice. We then studied H⁺-ATPase activity and trafficking in CDs. NH₃ uptake and H⁺ secretion were increased in the isolated in vitro microperfused CDs from chronic NH₄Cl-loaded Clcn5 KO mice. Furthermore, the a4 subunit of the vH⁺-ATPase was more present at the apical plasma membrane in cortical A-ICs from Clcn5 KO compared to WT mice.

Thus the lack of ClC-5 in mouse is not reflected by defective acid secretion in the CD but rather by a major increase in acid secretion, mediated by enhanced vH⁺ATPase trafficking to the apical plasma membrane of A-IC, probably to compensate for the generalized PT defect.