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A mouse model for the renal salt-wasting syndrome pseudohypoaldosteronism
Proceedings of the National Academy of Sciences of the United States of America
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Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. --- Old month value: Oct 14
Aldosterone-dependent epithelial sodium transport in the distal nephron is mediated by the absorption of sodium through the highly selective, amiloride-sensitive epithelial sodium channel (ENaC) made of three homologous subunits (alpha, beta, and gamma). In human, autosomal recessive mutations of alpha, beta, or gammaENaC subunits cause pseudohypoaldosteronism type 1 (PHA-1), a renal salt-wasting syndrome characterized by severe hypovolemia, high plasma aldosterone, hyponatremia, life-threatening hyperkaliemia, and metabolic acidosis. In the mouse, inactivation of alphaENaC results in failure to clear fetal lung liquid at birth and in early neonatal death, preventing the observation of a PHA-1 renal phenotype. Transgenic expression of alphaENaC driven by a cytomegalovirus promoter in alphaENaC(-/-) knockout mice [alphaENaC(-/-)Tg] rescued the perinatal lethal pulmonary phenotype and partially restored Na+ transport in renal, colonic, and pulmonary epithelia. At days 5-9, however, alphaENaC(-/-)Tg mice showed clinical features of severe PHA-1 with metabolic acidosis, urinary salt-wasting, growth retardation, and 50% mortality. Adult alphaENaC(-/-)Tg survivors exhibited a compensated PHA-1 with normal acid/base and electrolyte values but 6-fold elevation of plasma aldosterone compared with wild-type littermate controls. We conclude that partial restoration of ENaC-mediated Na+ absorption in this transgenic mouse results in a mouse model for PHA-1.
Amiloride/pharmacology Animals Animals, Newborn Disease Models, Animal Electrophysiology Epithelial Sodium Channel Fetal Death Genes, Recessive Heterozygote Humans Kidney/pathology/physiopathology Lung/pathology/physiology/*physiopathology Membrane Potentials/drug effects/physiology Mice Mice, Knockout Mice, Transgenic Mucous Membrane/drug effects/physiology/physiopathology Pseudohypoaldosteronism/*genetics/pathology/*physiopathology Sodium Channels/biosynthesis/*deficiency/*genetics Survival Rate
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