Impaired renal HCO<sub>3</sub><sup>−</sup> secretion in CFTR deficient mice causes metabolic alkalosis during chronic base‐loading
Peder Berg, Samuel L. Svendsen, Thi Thuy Linh Hoang, Helle A. Prætorius, Mads Vaarby Sørensen, Jens Leipziger
Abstract
Abstract Aim Cystic fibrosis patients have an increased risk of developing metabolic alkalosis presumably as a result of altered renal HCO 3 − handling. In this study, we directly assess the kidneys’ ability to compensate for a chronic base‐load in the absence of functional CFTR. Methods Comprehensive urine and blood acid‐base analyses were done in anaesthetized WT mice or mice lacking either CFTR or pendrin, with or without 7 days of oral NaHCO 3 loading. The in vivo experiments were complemented by a combination of immunoblotting and experiments with perfused isolated mouse cortical collecting ducts (CCD). Results Base‐loaded WT mice maintained acid‐base homeostasis by elevating urinary pH and HCO 3 − excretion and decreasing urinary net acid excretion. In contrast, pendrin KO mice and CFTR KO mice were unable to increase urinary pH and HCO 3 − excretion and unable to decrease urinary net acid excretion sufficiently and thus developed metabolic alkalosis in response to the same base‐load. The expression of pendrin was increased in response to the base‐load in WT mice with a paralleled increased pendrin function in the perfused CCD. In CFTR KO mice, 7 days of base‐loading did not upregulate pendrin expression and apical Cl − /HCO 3 − exchange function was strongly blunted in the CCD. Conclusion CFTR KO mice develop metabolic alkalosis during a chronic base‐load because they are unable to sufficiently elevate renal HCO 3 − excretion. This can be explained by markedly reduced pendrin function in the absence of CFTR.