A MOUSE MODEL FOR THE RENAL SALT-WASTING SYNDROME PSEUDOHYPOALDOSTERONISM

Aldosterone-dependent epithelial sodium transport in the distal nephro n is mediated by the absorption of sodium through the highly selective , amiloride-sensitive epithelial sodium channel (ENaC) made of three h omologous subunits (alpha, beta, and gamma). In human, autosomal reces sive mutations of alpha, beta, or gamma ENaC subunits cause pseudohypo aldosteronism type 1 (PHA-1), a renal salt-wasting syndrome characteri zed by severe hypovolemia, high plasma aldosterone, hyponatremia, life -threatening hyperkaliemia, and metabolic acidosis, In the mouse, inac tivation of alpha ENaC results In failure to clear fetal lung liquid a t birth and in early neonatal death, preventing the observation of a P HA-1 renal phenotype, Transgenic expression of alpha ENaC driven by a cytomegalovirus promoter in alpha ENaC(-/-) knockout mice [alpha ENaC( -/-)Tg] rescued the perinatal lethal pulmonary phenotype and partially restored Na+ transport in renal, colonic, and pulmonary epithelia, At days 5-9, however, alpha ENaC(-/-)Tg mice showed clinical features of severe PHA-1 with metabolic acidosis, urinary salt-wasting, growth re tardation, and 50% mortality, Adult alpha ENaC(-/-)Tg survivors exhibi ted a compensated PHA-1 with normal acid/base and electrolyte values b ut 6-fold elevation of plasma aldosterone compared with wildtype litte rmate controls, We conclude that partial restoration of ENaC-mediated Na+ absorption in this transgenic mouse results in a mouse model for P HA-1.