The epithelial Na channel: a new player in the ...

REVIEW URRENT C OPINION

The epithelial Naþ channel: a new player in the vasculature Kristina Kusche-Vihrog a, Antoine Tarjus b, Johannes Fels a, and Fre´de´ric Jaisser b

Purpose of review Approximately 20 years ago, a paradigm shift occurred questioning whether expression of the epithelial Naþ channel (ENaC) was mainly restricted to epithelial tissues. In this review, the recent findings of ENaC regulation, and its potential contributions to the function and dysfunction of the vasculature, is discussed. Recent findings Over the last few years, the expression, localization, and functional properties of ENaC have been determined in the two main vascular cell types: endothelial cells, and vascular smooth muscle cells. A chronically increased ENaC membrane abundance can lead to endothelial stiffening and to a reduced release of nitric oxide, the hallmark of endothelial dysfunction. Endothelial ENaC was shown to determine vasoconstriction by negatively modulating nitric oxide release in mesenteric arteries, likely via the PI3K/Akt signaling pathway. ENaC has therefore been recognized as a potentially important regulator of vascular nanomechanics and as a transducer of mechanical forces. Summary As ENaC expression is broader than anticipated, it has become clear that the protein may play a crucial role in the vasculature as it is located at the interface between blood and tissue, and is therefore implicated in the development of endothelial dysfunction and hypertension. Keywords aldosterone, ENaC, endothelial cells, nitric oxide, shear stress

INTRODUCTION Up to now, the expression of the epithelial Naþ channel (ENaC) has been thought to be mainly restricted to epithelial tissues [1,2]. However, evidence has accumulated over the last few decades indicating a broader expression of ENaC which may reveal extended physiological and pathophysiological roles of the protein, and it has become clear that the protein plays a crucial role in the vasculature [3]. Defects in the Naþ transport mechanism via ENaC predispose all genetic and probably most common forms of human hypertension [4]. A classic example of genetically conditioned hypertension is Liddle’s syndrome [5,6]. Recently, it was shown that altered function of ENaC in the vascular endothelium, in addition to the kidney, contributes to the pathology of this disease [7 ,8]. The purpose of this review is to summarize our current understanding of the role of ENaC in the vascular beds and emphasize its potential role in blood vessel remodeling, blood flow regulation in the tissues, and in blood pressure control. &&

EPITHELIAL NaR CHANNEL EXPRESSION AND REGULATION IN ENDOTHELIAL CELLS About 20 years ago, the idea that ENaC expression was restricted to the epithelial tissues was questioned. First, indirect observations demonstrated the existence of an amiloride-sensitive channel in vascular endothelia; the morphology and surface area of vascular endothelial cells are modified by aldosterone [9], whereas aldosterone receptor antagonists [10,11] or specific blocker of ENaC [12] prevent these effects. Over the years, direct hints of the presence of ENaC in endothelial tissues a

Institute of Physiology II, University of Mu¨nster, Mu¨nster, Germany and INSERM U872 Team 1, Centre de Recherche des Cordeliers, Universite´ Rene´ Descartes, Universite´ Pierre et Marie Curie Paris, Paris Cedex 06, France b

Correspondence to Dr Kristina Kusche-Vihrog, Institute of Physiology II, University of Mu¨nster, Robert-Koch-Strasse 27b, 48149 Mu¨nster, Germany. Tel: +49 251 8355336; e-mail: [email protected] Curr Opin Nephrol Hypertens 2014, 23:143–148 DOI:10.1097/01.mnh.0000441054.88962.2c

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Pathophysiology of hypertension

KEY POINTS ENaC is expressed in the endothelial and vascular smooth muscle cells. Endothelial ENaC determines the mechanical properties of endothelial cells. Endothelial ENaC might transduce mechanical forces toward the endothelium.

have accumulated and the expression of ENaC in the endothelium has been reported by many groups [11–16]. The three different ENaC subunits (a, b, and g) have been identified in human umbilical vein endothelial cells (HUVECs, primary culture) by western blotting [11], endothelial cells of ex vivo mouse aortae preparations [7 ], and in different endothelial cell lines (EA.hy926 and HMEC) by RTPCR, western blotting, and immunofluorescence microscopy [16–18]. In small diameter rat mesenteric arteries, the expression and function of endothelial ENaC was also studied; three subunits have been detected by RT-PCR and western blotting, and, more importantly, amiloride/benzamil-sensitive Naþ currents have been characterized with patch clamp experiments [19]. Endothelial ENaC is regulated by aldosterone, similarly to epithelial ENaC in that the mineralocorticoid hormone triggers the membrane insertion of the channel, most likely via a mineralocorticoidreceptor-mediated pathway [13,20]. Indeed, endothelial expression of the mineralocorticoid receptor has been reported, indicating that the prerequisites for the regulation of ENaC by aldosterone are present in the endothelial cells [21,22]. Electrophysiological investigations in vascular endothelial cells have indicated that amiloride and benzamil functionally inhibit ENaC (i.e. Naþ influx into the cell) in the endothelial cells in a similar way to epithelial tissues [16,17,19]. Interestingly, amiloride and benzamil, two highly specific functional inhibitors of ENaC, determine the nanomechanical properties of endothelial cells, in that its application softens the endothelial cortex [7 ,20]. However, it has become obvious that the efficacy of amiloride is higher than that of benzamil which is not in accordance with the situation found in epithelial tissues [19]. This interesting finding could be indicative of the presence of nonclassical ENaC channels in the endothelium. The endothelial ENaC may be different from the epithelial ENaC; in vascular endothelium, in contrast to the kidney, the expression and membrane abundance of ENaC was &&

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increased by high extracellular Naþ concentrations (>145 mM) [17,23] instead of being reduced as a result of the well described feedback inhibition shown in epithelial tissues [24,25].

EPITHELIAL NaR CHANNEL EXPRESSION AND REGULATION IN VASCULAR SMOOTH MUSCLE CELLS The expression and the role of ENaC in the vascular smooth muscle cells (VSMCs) are still debated. In vivo, several studies have shown ENaC expression in VSMCs from different vascular beds. The protein expression of all three subunits (a, b, and g) was reported in the VSMCs of rat mesenteric arteries [26,27]. Perez et al. [19] also identified the three subunits in the VSMCs of rat mesenteric arteries by RT-PCR, western blotting, and immunolocalization, while in rat cerebral vessels, only b and g subunits were identified by western blotting and immunolocalization [28]. Interestingly, a variable expression of the ENaC subunits was reported in the mouse between freshly isolated VSMCs from renal interlobar arteries and primary culture from the same vascular bed, although the three subunits are expressed in primary culture, only b and g ENaC subunits could be identified in freshly isolated cells. This differential expression was also found in different VSM cell lines of VSMCs; only b and g ENaC subunits were detected by immunolocalization in SV40-LT immortalized VSMCs, whereas all three subunits were found in the A10 cell line. Inhibition of ENaC (using benzamil) in these cell lines prevented cell invasion associated with wound healing in SV40-LT VSMCs and cell migration in A10 cells. siRNA targeting of each subunit one-by-one, indicated that all subunits are involved in these processes [29]. Up to now, the regulation of a, b, and g ENaC expression in VSMCs, particularly the modulation of expression by aldosterone, has not been explored. Interestingly, in contrast to what is known for ENaC regulation in endothelial cells, high salt intake has been shown to decrease the expression of a and g ENaC, while it triggers the translocation of the b ENaC subunit toward the membrane of VSMCs [30]. In conclusion, there is little in the literature related to ENaC expression in the vasculature. Although there is now evidence of the presence of the epithelial sodium channel in endothelial cells as well as in the smooth muscle cells, parts of the puzzle are still missing. The pattern of expression of the different subunits seems to differ depending on the vascular beds that are explored. The environment of the cell and whether expression is analyzed in isolated or cultured cells or in situ in the vessel Volume 23 Number 2 March 2014


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might explain some of the discrepancies. The role of extracellular matrix adhesion and cell–cell interaction may participate in ENaC expression in the context of a mechano-sensing complex.

EPITHELIAL NaR CHANNEL AS A TRANSDUCER OF SHEAR STRESS ENaC determines the nanomechanical properties of endothelial cells as its membrane abundance is correlated to the stiffness of the cellular cortex, a compartment of about 50–100 nm underneath the plasma membrane; the more ENaC, the stiffer the cortex [3,7 ]. Endothelial cells form the inner layer of blood vessels and are exposed to the shear stress derived from the hemodynamic forces of the blood flow. Stiff endothelial cells are less deformable by the streaming blood than soft cells, resulting in a reduced stimulation of the endothelial nitric oxide synthase (eNOS) and, in turn, a reduced secretion of the vasodilating gas nitric oxide. Therefore, stiff endothelial cells release less nitric oxide than soft endothelial cells [23,31,32]. After synthesis and release, nitric oxide diffuses to adjacent VSMCs where it triggers vasodilation via a cGMP-dependent pathway [33]. In the case of reduced nitric oxide release, vasodilation of the vessel is impaired, a hallmark of endothelial dysfunction, also named ‘stiff endothelial cell syndrome’ (SECS) [34]. If this situation persists, hypertension might develop. Another factor influencing the nitric oxide release is the cortical actin web underneath the plasma membrane. A shift from depolymerized actin (G-actin) to polymerized actin (F-actin) relates to the degree of endothelial cortical stiffness and nitric oxide production [35 ]. As the C-terminus of ENaC interacts with cortical F-actin [36,37], a model is proposed as follows: increased membrane abundance of ENaC stiffens the endothelial cortex, likely via interaction with proteins of the cortical web, and in turn prevents the release of nitric oxide, leading to the vasoconstriction of the vessel (see Fig. 1). ENaC is a member of the degenerin protein family as indicated by structural homologies. Some members of this family have been described as mechanosensor in other species, such as the nematode Caenorhabditis elegans. The activity and expression of ENaC itself is enhanced by the laminar flow compared with the static conditions [16]. Taken together, these observations lead to the conclusion that the presence or absence of ENaC in the endothelial membrane is critical for the functional plasticity of the cell. Thus, it is hypothesized that ENaC translates the signal derived from the lumen of the vessel, in that it modifies the mechanical properties of the endothelium. Shear stress is &&

&

converted into biochemical signals through various membrane-associated molecules and transmitted into the interior of the cell via downstream pathways, leading to changes in gene expression through the activation of a variety of transcriptional factors [38]. A major component of shear stress sensing is the endothelial glycocalyx (eGC) which is located on top of the endothelial cell and is connected with the proteins of the cortical web [39 ]. The eGC is composed of negatively charged membranous glycoproteins, proteoglycans, glycoaminoglycans, and associated plasma proteins [40]. Thus, shear stress affects the conformation of the eGC and, as a result, an appropriate signal is transmitted through intracellular domains of the eGC to the cortical cytoskeleton [41]. From these results, it can be hypothesized that endothelial ENaC and the eGC could act together as endothelial shear-stress sensors. &

IMPLICATION OF EPITHELIAL NaR CHANNELS IN VASCULAR REACTIVITY AND BEYOND Expression of ENaC in the vasculature raises the question of its functional role in vascular physiology and disease. The two main adaptative mechanisms to mechanical forces in the vasculature are the endothelium-induced dilatory response to increased laminar shear stress and the VSMC-induced constriction in response to increased intraluminal pressure (myogenic tone). ENaC activity, as measured by patch clamp, is modulated by endothelial shear stress [16]. However, the role of endothelial ENaC in shear stress sensing in vivo has not been explored. However, a physiological role of ENaC in the VSMCs has been described. In ex-vivo rat cerebral arteries, ENaC blockers (such as amiloride or the more specific inhibitor benzamil) inhibit a major part of myogenic tone [28]. The same observation has been reported in ex-vivo mouse renal interlobar arteries [26]. In rat mesenteric arteries, however, pharmacological inhibition of ENaC did not inhibit myogenic tone at basal state. The role of ENaC on myogenic tone was analyzed in rats with a high salt diet (8% NaCl for 2 weeks). High salt diet did not alter the myogenic tone per se, but increased the part of myogenic tone mediated by ENaC and blocked by benzamil [30]. Vascular reactivity is also mediated through vasoactive responses to pharmacological agents. In ex-vivo rat mesenteric arteries, inhibition of ENaC by amiloride or benzamil inhibits the constriction response to phenylephrine (an a-adrenergic agonist) and serotonin [19]. This has been proposed as a secondary effect related to an increased vasodilation. Indeed, amiloride and, to a lesser extent,



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Blood flow

Na+

Na+

Gene expression ↑

ENaC

eNOS

Cortical F-actin

PI3K / Akt

Plasma membrane eNOS Endothelial NO synthase E NaC

Mechanotransduction

NO ENaC

ENaC

Na+

Cortical actin web Glycocalyx

Epithelial Na+ channel Nucleus

FIGURE 1. A model showing how endothelial ENaC determines the mechanical properties of the cell cortex. ENaC plays a crucial role in vascular function as it determines the cortical stiffness of vascular endothelial cells, which in turn controls the NO production and thus vascular function. Possible mechanisms include its interaction with F-actin and the inhibition of the PI3K/Akt signaling pathway. The endothelial glycocalyx (eGC) is located on the top of endothelial cells and serves as shear stress sensor and transduces the signal toward the interior of the cell. As the eGC is also connected with proteins of the cortical web, it is hypothesized that ENaC and eGC act together as endothelial shear-stress sensors. NO, nitric oxide.

benzamil induced a dose-dependent relaxation in rat mesenteric arteries. This is because of an increase in the activation of the PI3K/Akt/eNOS pathway; ENaC antagonists increase the phosphorylation of AKT and eNOS as well as vascular nitric oxide production. A PI3 kinase inhibitor blocks these effects. This suggests a role of negative control for ENaC on nitric-oxidedependent vasodilation. The use of pharmacological tools limits the possibility to dissect the implication of each subunit in the ENaC-mediated effects and to determine the role of endothelium versus VSMC. Moreover, the pharmacological approach prevents the study of vascular ENaC in integrative physiology independently of the renal tubular effect of ENaC activity. Considering the systemic effect of pharmacological inhibition of ENaC (effect on sodium reabsorption at the kidney level as well as inhibition in other targets) or global mouse inactivation models, it is difficult to determine the involvement of vascular ENaC in vascular physiology and physiopathology. To dissect the role of the b ENaC subunit in the myogenic tone, a transgenic mouse model with global downexpression (50%) of b ENaC was used; in cerebral arteries, the myogenic response to 146


intraluminal pressure increase is reduced by more than 50% [42]. Similar results have been observed in the afferent and interlobar arteries of these mutant mice [43 ]. b ENaC subunit downregulation altered the renal blood flow autoregulation. This is associated with an increase in blood pressure (which may be because of altered baroreflex) and in renal macrophage infiltration. The role of endothelial ENaC in the pathophysiological situations (flow-mediated vascular remodeling, leucocyte–endothelium interactions, and hypertension or atherosclerosis) is still unknown and deserves investigation. &

CONCLUSION It is now well established that ENaC is expressed in the vasculature and plays a role in vascular physiology, but its participation in vascular pathophysiology and diseases is still unclear. Despite the progress made since the early 2000s, many questions are still unanswered. The expression and regulation of each subunit in the vessels remains to be defined; the expression pattern seems to depend on the vascular beds and its cellular environment. ENaC is proposed to transduce mechanical forces; its link Volume 23 Number 2 March 2014


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to the extracellular matrix and to cell cytoskeleton could be a major factor in its expression and regulation. Are the three ENaC subunits crucial for the channel activity in every cell type? What is the stoichiometry of vascular ENaC subunits? Does vascular ENaC act like a Naþ channel? Could aldosterone regulate ENaC in the vasculature as it does in the kidney? What are the diseases related to the modulation of ENaC activity in the vessel? These questions need to be addressed carefully, with the help of conditional mouse models with cell-specific inactivation of the various subunits in physiological and pathophysiological settings. This will help in our understanding of the role of vascular ENaC (and the potential benefit of its inhibition) in diseases. Acknowledgements None. Conflicts of interest This work was supported by grants from the Deutsche Forschungsgemeinschaft (Koselleck-OB 63/18, KU 1496/7-1), the ‘Innovative Medical Research’ of the University of Muenster Medical School (KU 120808) and the Else-Kro¨ner-Fresenius Stiftung (2010 A116), the ‘AgenceNationale pour la Recherche’ (ANR09-BLAN-0156-01), and the COST Action ADMIRE BM1301. There are no conflicts of interest.

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