The epithelial sodium channel (ENaC): Mediator of the aldosterone response 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).
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2019, Metabolism: Clinical and ExperimentalCitation Excerpt :This, in turn, promoted Na+ entry into ECs which induced polymerization of G-actin to F-actin [3,7]. Such cytoskeletal remodeling is thought to repress calveolar eNOS activity which reduces NO production, resulting in EC remodeling of the actin cytoskeleton and excessive endothelium stiffness [3,29,31]. Our recent studies have shown that in vivo global inhibition of ENaC with amiloride [21] and EC specific deletion of αEnNaC−/− [7] prevents MR mediated arterial stiffness and improves flow-induced resistant artery dilation.
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2014, Biochimica et Biophysica Acta - Molecular Basis of DiseaseCitation Excerpt :Consistently, MRAs have been shown to prevent overall arterial stiffness [119] and the application of spironolactone has been reported to prevent the ‘stiff endothelial cell syndrome’ [124]. Endothelial stiffness can be assessed in vitro and ex vivo by using the atomic force microscope (AFM) as a nanosensor [56,118]. Our group has recently reported that the expression of genes regulating endothelial stiffness depends on sAC [8].
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