Salt restriction induces pseudohypoaldosteronism type 1 in mice expressing low levels of the beta-subunit of the amiloride-sensitive epithelial sodium channel.
The amiloride-sensitive epithelial sodium channel (ENaC) is a heteromultimer of three homologous subunits (alpha-, beta-, and gamma-subunits). To study the role of the beta-subunit in vivo, we analyzed mice in which the betaENaC gene locus was disrupted. These mice showed low levels of betaENaC mRNA expression in kidney (approximately 1%), lung (approximately 1%), and colon (approximately 4%). In homozygous mutant betaENaC mice, no betaENaC protein could be detected with immunofluorescent staining. At birth, there was a small delay in lung-liquid clearance that paralleled diminished amiloride-sensitive Na+ absorption in tracheal explants. With normal salt intake, these mice showed a normal growth rate. However, in vivo, adult betaENaC m/m mice exhibited a significantly reduced ENaC activity in colon and elevated plasma aldosterone levels, suggesting hypovolemia and pseudohypoaldosteronism type 1. This phenotype was clinically silent, as betaENaC m/m mice showed no weight loss, normal plasma Na+ and K+ concentrations, normal blood pressure, and a compensated metabolic acidosis. On low-salt diets, betaENaC-mutant mice developed clinical symptoms of an acute pseudohypoaldosteronism type 1 (weight loss, hyperkalemia, and decreased blood pressure), indicating that betaENaC is required for Na+ conservation during salt deprivation.
Pradervand
S
S
Institut de Pharmacologie et de Toxicologie, Université de Lausanne, Rue du Bugnon 27, 1005 Lausanne, Switzerland.
Barker
P M
PM
Wang
Q
Q
Ernst
S A
SA
Beermann
F
F
Grubb
B R
BR
Burnier
M
M
Schmidt
A
A
Bindels
R J
RJ
Gatzy
J T
JT
Rossier
B C
BC
Hummler
E
E
D000450:Aldosterone / Q000097:blood; D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure; D001835:Body Weight; D003106:Colon / Q000378:metabolism; D004039:Diet, Sodium-Restricted; D053503:Epithelial Sodium Channels; D015698:Genomic Library; D005838:Genotype; D006720:Homozygote; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D011546:Pseudohypoaldosteronism / Q000235:genetics* / Q000503:physiopathology; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D014132:Trachea / Q000378:metabolism