Elsevier

Steroids

Volume 75, Issues 8–9, August–September 2010, Pages 544-549
Steroids

The epithelial sodium channel (ENaC): Mediator of the aldosterone response in the vascular endothelium?

https://doi.org/10.1016/j.steroids.2009.09.003Get rights and content

Abstract

In the kidney the epithelial sodium channel (ENaC) is regulated by the mineralocorticoid hormone aldosterone, which is essential for long-term blood pressure control. Evidence has accumulated showing that ENaC is expressed in endothelial cells. Moreover, its activity modifies the biomechanical properties of the endothelium. Therefore, the vascular system is also an important target for aldosterone and responds to the hormone with an increase in cell volume, surface area, and mechanical stiffness. These changes occur in a concerted fashion from minutes to hours and can be prevented by the specific sodium channel blocker amiloride and the mineralocorticoid receptor (MR) blocker spironolactone. Aldosterone acts on cells of the vascular system via genomic and non-genomic pathways. There is evidence that the classical cytosolic MR could mediate both types of response. Using a nanosensor covalently linked to aldosterone, binding sites at the plasma membrane were identified by atomic force microscopy. The interaction of aldosterone and this newly identified surface receptor could precede the slow classic genomic aldosterone response resulting in fast activation of endothelial ENaC. Recent data suggest that aldosterone-induced ENaC activation initiates a sequence of cellular events leading to a reduced release of vasodilating nitric oxide. We propose a model in which ENaC is the key mediator of aldosterone-dependent blood pressure control in the vascular endothelium.

Section snippets

ENaC is present in the vascular endothelium

One of the major targets of aldosterone in epithelia is the epithelial sodium channel (ENaC). After its cloning in 1995 by Canessa et al. [1] this channel was recognized as being an important regulator of sodium homeostasis and arterial blood pressure. It is the rate limiting mechanism of Na+ reabsorption in the kidney. ENaC consists of four different subunits (α, β, γ and δ) which are expressed in a tissue specific manner [2], [3], [4] and can be functionally blocked by of amiloride [5]. In

Aldosterone modifies vascular endothelium

In the human organism salt and water homeostasis is regulated by the mineralocorticoid hormone aldosterone and its cytosolic receptor (MR). The classical targets for aldosterone are the principal cells of the collecting duct where the steroid binds to the cytosolic receptor and triggers a signal cascade which induces the transcription of many aldosterone-responsive genes. As a result of this genomic aldosterone action a de novo synthesis of proteins is initialized. After a delay these

The mineralocorticoid receptor in endothelial cells: classic versus non-classic

Clearly, the genomic action of aldosterone in endothelial cells is mediated by the mineralocorticoid receptor. Over the past years there has been accumulating evidence that the classic cytosolic receptor could even account for both genomic and non-genomic responses [47], [48], [49]. Although serious attempts were made to identify a specific plasma membrane aldosterone receptor, the final proof for its existence is still missing [50]. Work in our laboratory indicates that in the very early phase

ENaC mediates aldosterone action in the endothelium

Aldosterone action in endothelial cells could lead to a sequence of events that result in increased stiffening of the cells, reduction of NO release and vasoconstriction of the vascular smooth muscle cells. As already mentioned indirect evidence led to the conclusion that ENaC mediates this cellular response (Table 1). Recently, in our laboratory a strong hint for a key role of ENaC as mediator of aldosterone-induced stiffening was found. We have stably knocked down the ENaC α-subunit in

Concluding remarks

There is evidence that ENaC plays a key role in vascular endothelial cells. Its surface expression and functional activity is regulated genomically and non-genomically by aldosterone. Fig. 5 shows a schematic model illustrating the sequence of events triggered by aldosterone-induced ENaC activation. In the slow genomic pathway aldosterone binds to the classical cytosolic mineralocorticoid receptor and induces the synthesis of new ENaC molecules. In parallel aldosterone also activates the

Acknowledgement

We are grateful to Dr. Nadine Bangel-Ruland for images from human nasal epithelial cells. This work was supported by Deutsche Forschungsgemeinschaft (OB63/17-1) and Innovative Medizinische Forschung an der medizinischen Fakultät Münster (KU 120808).

References (53)

  • D. Pesen et al.

    Modes of remodeling in the cortical cytoskeleton of vascular endothelial cells

    FEBS Lett

    (2005)
  • C. Grossmann et al.

    EF domains are sufficient for nongenomic mineralocorticoid receptor actions

    J Biol Chem

    (2008)
  • M. Wehling et al.

    Aldosterone-specific membrane receptors and rapid non-genomic actions of mineralocorticoids

    Mol Cell Endocrinol

    (1992)
  • C. Mazzochi et al.

    The carboxyl terminus of the alpha-subunit of the amiloride-sensitive epithelial sodium channel binds to F-actin

    J Biol Chem

    (2006)
  • F.J. McDonald et al.

    Cloning expression, and tissue distribution of a human amiloride-sensitive Na+ channel

    Am J Physiol

    (1994)
  • N. Bangel-Ruland et al.

    Characterization of the Epithelial Sodium Channel Delta Subunit in Human Nasal Epithelium

    Am J Respir Cell Mol Biol

    (2009)
  • D. Alvarez de la Rosa et al.

    Structure and regulation of amiloride-sensitive sodium channels

    Annu Rev Physiol

    (2000)
  • S.S. Chang et al.

    Mutations in subunits of the epithelial sodium channel cause salt wasting with hyperkalaemic acidosis, pseudohypoaldosteronism type 1

    Nat Genet

    (1996)
  • M. Mall et al.

    Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice

    Nat Med

    (2004)
  • A. May et al.

    Early effect of aldosterone on the rate of synthesis of the epithelial sodium channel a subunit in A6 renal cells

    J Am Soc Nephrol

    (1997)
  • D. Alvarez de la Rosa et al.

    Effects of aldosterone on biosynthesis, traffic, and functional expression of the epithelial sodium channel in A6 cells

    J Gen Physiol

    (2002)
  • V. McEneaney et al.

    Aldosterone regulates rapid trafficking of epithelial sodium channel subunits in renal cortical collecting duct cells via protein kinase D activation

    Mol Endocrinol

    (2008)
  • C. Debonneville et al.

    Phosphorylation of Nedd4-2 by Sgk1 regulates epithelial Na+ channel surface expression

    EMBO J

    (2001)
  • A. Diakov et al.

    Cleavage in the γ-subunit of the epithelial sodium channel (ENaC) plays an important role in the proteolytic activation of near-silent channels

    J Physiol

    (2008)
  • V. Vallet et al.

    An epithelial serine protease activates the amiloride-sensitive sodium channel

    Nature

    (1997)
  • H. Oberleithner et al.

    Differential action of steroid hormones on human endothelium

    J Cell Sci

    (2006)
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