Salt Restriction Induces Pseudohypoaldosteronism Type 1 in Mice Expressing Low Levels of the Beta-subunit of the Amiloride-sensitive Epithelial Sodium Channel

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 1999 Feb 17

PMID 9990093

Citations 46

Authors

S Pradervand

P M Barker

Q Wang

S A Ernst

F Beermann

B R Grubb

M Burnier

A Schmidt

R J Bindels

J T Gatzy

B C Rossier

E Hummler

Affiliations

Soon will be listed here.

Abstract

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.

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References

CHEEK D, Perry J . A salt wasting syndrome in infancy. Arch Dis Child. 1958; 33(169):252-6. PMC: 2012226. DOI: 10.1136/adc.33.169.252. View

Shaw G, Kamen R . A conserved AU sequence from the 3' untranslated region of GM-CSF mRNA mediates selective mRNA degradation. Cell. 1986; 46(5):659-67. DOI: 10.1016/0092-8674(86)90341-7. View

Olver R, Ramsden C, Strang L, Walters D . The role of amiloride-blockable sodium transport in adrenaline-induced lung liquid reabsorption in the fetal lamb. J Physiol. 1986; 376:321-40. PMC: 1182801. DOI: 10.1113/jphysiol.1986.sp016156. View

Rosler A . The natural history of salt-wasting disorders of adrenal and renal origin. J Clin Endocrinol Metab. 1984; 59(4):689-700. DOI: 10.1210/jcem-59-4-689. View

Renard S, Voilley N, Bassilana F, Lazdunski M, Barbry P . Localization and regulation by steroids of the alpha, beta and gamma subunits of the amiloride-sensitive Na+ channel in colon, lung and kidney. Pflugers Arch. 1995; 430(3):299-307. DOI: 10.1007/BF00373903. View

Schild L, Canessa C, Shimkets R, Gautschi I, Lifton R, Rossier B . A mutation in the epithelial sodium channel causing Liddle disease increases channel activity in the Xenopus laevis oocyte expression system. Proc Natl Acad Sci U S A. 1995; 92(12):5699-703. PMC: 41764. DOI: 10.1073/pnas.92.12.5699. View

Duc C, Farman N, Canessa C, Bonvalet J, Rossier B . Cell-specific expression of epithelial sodium channel alpha, beta, and gamma subunits in aldosterone-responsive epithelia from the rat: localization by in situ hybridization and immunocytochemistry. J Cell Biol. 1994; 127(6 Pt 2):1907-21. PMC: 2120291. DOI: 10.1083/jcb.127.6.1907. View

Shimkets R, Warnock D, Bositis C, Hansson J, Schambelan M, GILL Jr J . Liddle's syndrome: heritable human hypertension caused by mutations in the beta subunit of the epithelial sodium channel. Cell. 1994; 79(3):407-14. DOI: 10.1016/0092-8674(94)90250-x. View

Canessa C, Schild L, Buell G, Thorens B, Gautschi I, Horisberger J . Amiloride-sensitive epithelial Na+ channel is made of three homologous subunits. Nature. 1994; 367(6462):463-7. DOI: 10.1038/367463a0. View

10.

Hummler E, Cole T, Blendy J, Ganss R, Aguzzi A, Schmid W . Targeted mutation of the CREB gene: compensation within the CREB/ATF family of transcription factors. Proc Natl Acad Sci U S A. 1994; 91(12):5647-51. PMC: 44053. DOI: 10.1073/pnas.91.12.5647. View

11.

Canessa C, Horisberger J, Rossier B . Epithelial sodium channel related to proteins involved in neurodegeneration. Nature. 1993; 361(6411):467-70. DOI: 10.1038/361467a0. View

12.

Snyder P, Price M, McDONALD F, Adams C, Volk K, Zeiher B . Mechanism by which Liddle's syndrome mutations increase activity of a human epithelial Na+ channel. Cell. 1995; 83(6):969-78. DOI: 10.1016/0092-8674(95)90212-0. View

13.

Chang S, Grunder S, Hanukoglu A, Rosler A, Mathew P, Hanukoglu I . Mutations in subunits of the epithelial sodium channel cause salt wasting with hyperkalaemic acidosis, pseudohypoaldosteronism type 1. Nat Genet. 1996; 12(3):248-53. DOI: 10.1038/ng0396-248. View

14.

Hummler E, Barker P, GATZY J, Beermann F, Verdumo C, Schmidt A . Early death due to defective neonatal lung liquid clearance in alpha-ENaC-deficient mice. Nat Genet. 1996; 12(3):325-8. DOI: 10.1038/ng0396-325. View

15.

Strautnieks S, Thompson R, Gardiner R, Chung E . A novel splice-site mutation in the gamma subunit of the epithelial sodium channel gene in three pseudohypoaldosteronism type 1 families. Nat Genet. 1996; 13(2):248-50. DOI: 10.1038/ng0696-248. View

16.

Schild L, Lu Y, Gautschi I, Schneeberger E, Lifton R, Rossier B . Identification of a PY motif in the epithelial Na channel subunits as a target sequence for mutations causing channel activation found in Liddle syndrome. EMBO J. 1996; 15(10):2381-7. PMC: 450168. View

17.

Matsushita K, McCray Jr P, Sigmund R, Welsh M, Stokes J . Localization of epithelial sodium channel subunit mRNAs in adult rat lung by in situ hybridization. Am J Physiol. 1996; 271(2 Pt 1):L332-9. DOI: 10.1152/ajplung.1996.271.2.L332. View

18.

Kuhnle U, Hinkel G, Hubl W, Reichelt T . Pseudohypoaldosteronism: family studies to identify asymptomatic carriers by stimulation of the renin-aldosterone system. Horm Res. 1996; 46(3):124-9. DOI: 10.1159/000185008. View

19.

Firsov D, Schild L, Gautschi I, Merillat A, Schneeberger E, Rossier B . Cell surface expression of the epithelial Na channel and a mutant causing Liddle syndrome: a quantitative approach. Proc Natl Acad Sci U S A. 1996; 93(26):15370-5. PMC: 26411. DOI: 10.1073/pnas.93.26.15370. View

20.

Farman N, Talbot C, Boucher R, Fay M, Canessa C, Rossier B . Noncoordinated expression of alpha-, beta-, and gamma-subunit mRNAs of epithelial Na+ channel along rat respiratory tract. Am J Physiol. 1997; 272(1 Pt 1):C131-41. DOI: 10.1152/ajpcell.1997.272.1.C131. View