Molecular Mechanism of Augmented Renal Bicarbonate (HCO3-) Excretion During Respiratory Alkalosis

Background: During respiratory alkalosis, the kidneys increase urinary HCO3- excretion to regulate blood pH, as well demonstrated under high-altitude conditions. The molecular mechanism underlying this renal response remains unknown, but augmentation of renal HCO3- excretion during metabolic alkalosis was recently shown to depend on pendrin and CFTR in the collecting duct β-intercalated cells (β-ICs). Furthermore, secretin was shown to activate β-ICs. We hypothesized that β-IC pendrin is necessary for renal compensation of respiratory alkalosis. Methods: Under anesthesia, bladder-catheterized pendrin wildtype (WT) and knockout (KO) mice were mechanically ventilated to assess the renal response to hyperventilation-induced respiratory alkalosis. Additionally, intermittently-closed-flow respirometry was performed to quantify the ventilatory response of pendrin WT and KO mice to hypoxia. Results: A sharp increase in urine pH occurred shortly (i.e., 10-15 minutes) after initiation of hyperventilation in WT mice. This effect was completely absent in KO mice. Arterial blood gas analyses confirmed respiratory alkalosis during hyperventilation in both genotypes. Furthermore, KO mice displayed a reduced hyperventilatory response and larger body temperature decreases during hypoxia in intermittently-closed-flow respirometry. Conclusion: Our results demonstrate that β-IC pendrin function is necessary for the ability to increase urinary HCO3- excretion during respiratory alkalosis and that renal compensation initiates immediately. They also reveal that compromised β-IC function impairs ventilatory compensation to hypoxia, resulting in decreased metabolism. Hence, this study provides novel insights into the molecular mechanisms of renal compensation of respiratory alkalosis and their importance during hypoxia. Funding: Private Foundation Support, Government Support – Non-U.S.End-tidal CO2 and urine pH in pendrin WT and KO mice during hyperventilation