Dysregulation of Pendrin and NBC‐e1 and Impaired HCO3− Secretion in the Kidneys of CFTR Knockout Mice: Role in the pathogenesis of metabolic alkalosis in cystic fibrosis

Abstract

IntroductionPatients with cystic fibrosis (CF) are prone to the development of metabolic alkalosis, which is manifested by an elevation of arterial blood pH and bicarbonate concentration and produces a physiologic diminution of respiratory effort that is detrimental in CF patients. The pathogenesis of metabolic alkalosis in CF remains unknown.HypothesisInactivation of CFTR will impair the ability of the kidney to excrete excess bicarbonate via dysregulation of HCO3− transporters, therefore resulting in the elevation of arterial pH and bicarbonate concentration and subsequently, generation of metabolic alkalosis in mutant mice subjected to an oral bicarbonate load.MethodsCFTR knockout (CF) mice with the intestinal rescue (over‐expressing wild type CFTR transgene in their intestine‐Science 1994) were examined for the changes in arterial pH and bicarbonate concentration as well as the expression of pendrin and NBC‐e1. Animals were subjected to an oral bicarbonate load (140 mM/lit bicarbonate in the drinking water) and examined after 3 days.ResultsBaseline parameters, including acid‐base status and urine pH were comparable in CF and WT mice. Compared to WT animals, CF mice demonstrated a significant increase in blood HCO3− concentration (21.87 +/− 0.8 in wt vs. 26.83 +/− 0.9 mEq/l in CF mice, p<0.004) and pH (7.33 +/− 0.01 in wt vs. 7.42 +/− 0.02 in CF mice, p<0.003) and impaired kidney HCO3− excretion (urine pH 8.10 +/− 0.09 in wt vs. 7.35 +/− 0.09 in CF‐KO mice, p<0.002) following a 3‐day oral bicarbonate load. Immunofluorescence labeling demonstrated profound reduction in the apical expression and increased cytoplasmic and basolateral localization of pendrin in the intercalated cells in CF mice (Fig. 1). Moreover, an unexpected aberrant induction of the Na+:HCO3− co‐transporter NBCe1 (kidney NBC1) was detected in principal cells of the cortical collecting duct in CF mice (Fig. 2).ConclusionWe propose that patients with cystic fibrosis are prone to the development of metabolic alkalosis secondary to the dysregulation of pendrin and NBC‐e1, specifically during volume depletion, which is a common occurrence in CF patients.Support or Funding InformationMerit Review Award from Veterans Administration