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      In Liddle Syndrome, Epithelial Sodium Channel Is Hyperactive Mainly in the Early Part of the Aldosterone-Sensitive Distal Nephron.

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          Abstract

          The epithelial sodium channel (ENaC) is rate limiting for Na(+) absorption in the aldosterone-sensitive distal nephron comprising the late distal convoluted tubule (DCT2), the connecting tubule (CNT), and the entire collecting duct. Liddle syndrome (pseudohyperaldosteronism), a severe form of salt-sensitive hypertension, is caused by gain-of-function mutations of ENaC, but the precise tubular site of increased ENaC function is unknown. In the cortical collecting duct (CCD), ENaC is known to be regulated by aldosterone. In contrast, we recently reported aldosterone-independent ENaC regulation in the early part of the aldosterone-sensitive distal nephron. Here, we investigated ENaC function in the transition zone of DCT2/CNT or CNT/CCD microdissected from mice homozygous for Liddle syndrome mutation or from wild-type control mice. Whole-cell patch-clamp recordings were used to measure amiloride-sensitive ENaC currents in nephron fragments from mice maintained on different sodium diets to vary plasma aldosterone levels. Our data indicate that in mice with Liddle syndrome, the primary site of increased Na(+) reabsorption is the DCT2/CNT. In addition, increased aldosterone responsiveness of ENaC in CNT/CCD may contribute to salt-sensitive hypertension in Liddle syndrome. Single channel properties of ENaC were similar in Liddle syndrome mutation and wild-type mice, but ENaC expression at the apical membrane was increased in Liddle syndrome mutation when compared with wild-type mice, in particular, in animals maintained on a high salt diet. Our findings highlight the importance of ENaC function and regulation in the early part of the aldosterone-sensitive distal nephron for the maintenance of sodium balance and blood pressure control.

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          Author and article information

          Journal
          Hypertension
          Hypertension (Dallas, Tex. : 1979)
          Ovid Technologies (Wolters Kluwer Health)
          1524-4563
          0194-911X
          June 2016
          : 67
          : 6
          Affiliations
          [1 ] From the Institut für Zelluläre und Molekulare Physiologie (V.N., B.K., M.B., C.K.), Universitätsklinikum Erlangen, Medizinische Klinik 4-Nephrologie und Hypertensiologie (A.D.), and Optical Imaging Center Erlangen (OICE) (R.P.), Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
          [2 ] From the Institut für Zelluläre und Molekulare Physiologie (V.N., B.K., M.B., C.K.), Universitätsklinikum Erlangen, Medizinische Klinik 4-Nephrologie und Hypertensiologie (A.D.), and Optical Imaging Center Erlangen (OICE) (R.P.), Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany. christoph.korbmacher@fau.de.
          Article
          67/6/1256
          10.1161/HYPERTENSIONAHA.115.07061
          27170740

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