A mouse model for the renal salt-wasting syndrome pseudohypoaldosteronism.
- Hummler E Institut de Pharmacologie et de Toxicologie de l'Université, Rue du Bugnon 27, CH-1005 Lausanne, Switzerland. ehummler@pop-seiver.unil.ch
- Barker P
- Talbot C
- Wang Q
- Verdumo C
- Grubb B
- Gatzy J
- Burnier M
- Horisberger JD
- Beermann F
- Boucher R
- Rossier BC
- 1997-10-23
Published in:
- Proceedings of the National Academy of Sciences of the United States of America. - 1997
Amiloride
Animals
Animals, Newborn
Disease Models, Animal
Electrophysiology
Epithelial Sodium Channels
Fetal Death
Genes, Recessive
Heterozygote
Humans
Kidney
Lung
Membrane Potentials
Mice
Mice, Knockout
Mice, Transgenic
Mucous Membrane
Pseudohypoaldosteronism
Sodium Channels
Survival Rate
English
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.
- Language
-
- English
- Open access status
- bronze
- Identifiers
-
- DOI 10.1073/pnas.94.21.11710
- PMID 9326675
- Persistent URL
- https://sonar.ch/global/documents/277718
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