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      Chronic angiotensin II infusion drives extensive aldosterone-independent epithelial Na+ channel activation.

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          Abstract

          The inability of mineralocorticoid receptor (MR) blockade to reduce hypertension associated with high angiotensin (Ang) II suggests direct actions of Ang II to regulate tubular sodium reabsorption via the epithelial Na(+) channel (ENaC) in the aldosterone-sensitive distal nephron. We used freshly isolated aldosterone-sensitive distal nephron from mice to delineate the synergism and primacy between aldosterone and Ang II in controlling functional ENaC activity. Inhibition of MR specifically prevented the increased number of functionally active ENaC, but not ENaC open probability elicited by a low sodium diet. In contrast, we found no functional role of glucocorticoid receptors in the regulation of ENaC activity by dietary salt intake. Simultaneous inhibition of MR and Ang II type 1 receptors ameliorated the enhanced ENaC activity caused by low dietary salt intake and produced significantly greater natriuresis than either inhibitor alone. Chronic systemic Ang II infusion induced more than 2 times greater increase in ENaC activity than observed during dietary sodium restriction. Importantly, ENaC activity remained greatly above control levels during maximal MR inhibition. We conclude that during variations in dietary salt intake both aldosterone and Ang II contribute complementarily to the regulation of ENaC activity in the aldosterone-sensitive distal nephron. In contrast, in the setting of Ang II-dependent hypertension, ENaC activity is upregulated well above the physiological range and is not effectively suppressed by inhibition of the aldosterone-MR axis. This provides a mechanistic explanation for the resistance to MR inhibition that occurs in hypertensive subjects having elevated intrarenal Ang II levels.

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          Author and article information

          Journal
          Hypertension
          Hypertension (Dallas, Tex. : 1979)
          Ovid Technologies (Wolters Kluwer Health)
          1524-4563
          0194-911X
          Dec 2013
          : 62
          : 6
          Affiliations
          [1 ] Department of Integrative Biology and Pharmacology; The University of Texas Health Science Center at Houston, USA.
          [2 ] Department of Physiology and Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, LA, USA.
          [3 ] Center for Laboratory Animal Medicine and Care The University of Texas Health Science Center at Houston, USA.
          [4 ] Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, USA.
          Article
          NIHMS541902
          10.1161/HYPERTENSIONAHA.113.01797
          3889165
          24060890

          collecting duct, hypertension, nephrons

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