Aldosterone responsiveness of the epithelial sodium channel (ENaC) in colon is increased in a mouse model for Liddle's syndrome

• Published in: The Journal of physiology 2008-01, Vol.586 (2), p.459-475
• Main Authors: Bertog, Marko, Cuffe, John E., Pradervand, Sylvain, Hummler, Edith, Hartner, Andrea, Porst, Markus, Hilgers, Karl F., Rossier, Bernard C., Korbmacher, Christoph
• Format: Article
• Language: English
• Subjects: Aldosterone - blood; Aldosterone - physiology; Animals; Cellular; Colon - metabolism; Disease Models, Animal; Epithelial Sodium Channels - genetics; Epithelial Sodium Channels - metabolism; Female; Hypertension - genetics; Hypertension - metabolism; Hypokalemia - genetics; Hypokalemia - metabolism; Immediate-Early Proteins - metabolism; Kidney - metabolism; Lung - metabolism; Male; Mice; Mice, Mutant Strains; Protein-Serine-Threonine Kinases - metabolism; Renin - blood; Renin - genetics; Sodium, Dietary - pharmacology; Syndrome
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/jphysiol.2007.140459

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 (Δ I SC-Ami ) ex vivo . In Liddle mice maintained on a standard salt diet, Δ 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 Δ 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 Δ 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 β- and γ-subunit (βENaC and γENaC) 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 α-subunit (αENaC). 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.