Disruption of the β Subunit of the Epithelial Na+Channel in Mice: Hyperkalemia and Neonatal Death Associated with a Pseudohypoaldosteronism Phenotype

The epithelial Na+channel (ENaC) is composed of three homologous subunits: α,β and γ . We used gene targeting to disrupt the β subunit gene of ENaC in mice. The β ENaC-deficient mice showed normal prenatal development but died within 2 days after birth, most likely of hyperkalemia. In the -/- mice, we found an increased urine Na+concentration despite hyponatremia and a decreased urine K+concentration despite hyperkalemia. Moreover, serum aldosterone levels were increased. In contrast to α ENaC-deficient mice, which die because of defective lung liquid clearance, neonatal β ENaC deficient mice did not die of respiratory failure and showed only a small increase in wet lung weight that had little, if any, adverse physiologic consequence. The results indicate that, in vivo, the β subunit is required for ENaC function in the renal collecting duct, but, in contrast to the α subunit, the β subunit is not required for the transition from a liquid-filled to an air-filled lung. The phenotype of the β ENaC-deficient mice is similar to that of humans with pseudohypoaldosteronism type 1 and may provide a useful model to study the pathogenesis and treatment of this disorder.