A mouse model for the renal salt-wasting syndrome pseudohypoaldosteronism.
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.
Hummler
E
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
P
Talbot
C
C
Wang
Q
Q
Verdumo
C
C
Grubb
B
B
Gatzy
J
J
Burnier
M
M
Horisberger
J D
JD
Beermann
F
F
Boucher
R
R
Rossier
B C
BC
D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D004594:Electrophysiology; D053503:Epithelial Sodium Channels; D005313:Fetal Death; D005808:Genes, Recessive; D006579:Heterozygote; D006801:Humans; D007668:Kidney / Q000473:pathology / Q000503:physiopathology; D008168:Lung / Q000473:pathology / Q000502:physiology / Q000503:physiopathology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009092:Mucous Membrane / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology; D011546:Pseudohypoaldosteronism / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D015222:Sodium Channels / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*; D015996:Survival Rate
D053503:Epithelial Sodium Channels; D015222:Sodium Channels; D000584:Amiloride