title: Aldosterone responsiveness of the epithelial sodium channel (ENaC) in colon is increased in a mouse model for Liddle's syndrome.
abstract: Liddle's syndrome is an autosomal dominant form of human hypertension, caused by gain-of-function mutations of the epithelial sodium channel (ENaC) which is expressed in aldosterone target tissues including the distal colon. We used a mouse model for Liddle's syndrome to investigate ENaC-mediated Na+ transport in late distal colon by measuring the amiloride-sensitive transepithelial short circuit current (Delta I SC-Ami) ex vivo. In Liddle mice maintained on a standard salt diet, Delta I SC-Ami was only slightly increased but plasma aldosterone (P Aldo) was severely suppressed. Liddle mice responded to a low or a high salt diet by increasing or decreasing, respectively, their P Aldo and Delta I SC-Ami. However, less aldosterone was required in Liddle animals to achieve similar or even higher Na+ transport rates than wild-type animals. Indeed, the ability of aldosterone to stimulate Delta I SC-Ami was about threefold higher in Liddle animals than in the wild-type controls. Application of aldosterone to colon tissue in vitro confirmed that ENaC stimulation by aldosterone was not only preserved but enhanced in Liddle mice. Aldosterone-induced transcriptional up-regulation of the channel's beta- and gamma-subunit (beta ENaC and gamma ENaC) and of the serum- and glucocorticoid-inducible kinase 1 (SGK1) was similar in colon tissue from Liddle and wild-type animals, while aldosterone had no transcriptional effect on the alpha-subunit (alpha ENaC). Moreover, Na+ feedback regulation was largely preserved in colon tissue of Liddle animals. In conclusion, we have demonstrated that in the colon of Liddle mice, ENaC-mediated Na+ transport is enhanced with an increased responsiveness to aldosterone. This may be pathophysiologically relevant in patients with Liddle's syndrome, in particular on a high salt diet, when suppression of P Aldo is likely to be insufficient to reduce Na+ absorption to an appropriate level.
authors.affiliation: Institut für Zelluläre und Molekulare Physiologie, Waldstr. 6, 91054 Erlangen, Germany.
authors.forename: Marko
authors.initials: M
authors.lastname: Bertog
authors.forename: John E
authors.initials: JE
authors.lastname: Cuffe
authors.forename: Sylvain
authors.initials: S
authors.lastname: Pradervand
authors.forename: Edith
authors.initials: E
authors.lastname: Hummler
authors.forename: Andrea
authors.initials: A
authors.lastname: Hartner
authors.forename: Markus
authors.initials: M
authors.lastname: Porst
authors.forename: Karl F
authors.initials: KF
authors.lastname: Hilgers
authors.forename: Bernard C
authors.initials: BC
authors.lastname: Rossier
authors.forename: Christoph
authors.initials: C
authors.lastname: Korbmacher
mesh_terms: D000450:Aldosterone / Q000097:blood* / Q000502:physiology; D000818:Animals; D003106:Colon / Q000378:metabolism*; D004195:Disease Models, Animal; D053503:Epithelial Sodium Channels / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006973:Hypertension / Q000235:genetics / Q000378:metabolism*; D007008:Hypokalemia / Q000235:genetics / Q000378:metabolism*; D017874:Immediate-Early Proteins / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012083:Renin / Q000097:blood* / Q000235:genetics; D012982:Sodium, Dietary / Q000494:pharmacology*; D013577:Syndrome; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D000450:Aldosterone; D053503:Epithelial Sodium Channels; D017874:Immediate-Early Proteins; D017346:Protein Serine-Threonine Kinases; D012083:Renin; D012982:Sodium, Dietary; D000099184:Serum-Glucocorticoid Regulated Kinases