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This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 586/2/459    most recent jphysiol.2007.140459v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Bertog, M. Articles by Korbmacher, C. Search for Related Content PubMed PubMed Citation Articles by Bertog, M. Articles by Korbmacher, C. Related Collections Cellular

¹ Institut für Zelluläre und Molekulare Physiologie
² Medizinische Klinik 4, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany
³ University Laboratory of Physiology, Oxford University, Oxford OX1 3PT, UK
⁴ Institut de Pharmacologie et Toxicologie, Université de Lausanne, CH-1005 Lausanne, Switzerland

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 (I_SC-Ami) ex vivo. In Liddle mice maintained on a standard salt diet, 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 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 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 -subunit (βENaC and 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 -subunit (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.

(Received 11 July 2007; accepted after revision 12 November 2007; first published online 15 November 2007)
Corresponding author C. Korbmacher: Institut für Zelluläre und Molekulare Physiologie, Waldstr. 6, 91054 Erlangen, Germany. Email: christoph.korbmacher{at}physiologie2.med.uni-erlangen.de