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Essay: Liddle syndrome

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  • Published: 12 October 2015*
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The epithelial sodium ion channel (ENaC) is a membrane-bounded ion-channel. It is permeable for Li+ and Na+-ions. ENaC is highly active and selective Na+ channel. ENaC plays an important role in trans-epithelial sodium ion transport. This Na+ reabsorption is accomplished by Na+/K+ATPase. In vertebrates ENaC controls Na+ reabsorption in kidney, colon, lung and sweat glands; and play a role in taste perception. The activity of ENaC in kidney is regulated by the mineral-corticoid aldosterone and it can be inhibited by triamterene or amiloride. Therefore triamterene ENaC inhibitor and amiloride, Na+ transport inhibitor [1], are used as diuretics in medical field. In the kidney, it is inhibited by atrial natriuretic peptide, causing natriuresis and diuresis. ENaC is made up of three subunits which are ENaC??, ENaC ?? and ENaC ?? [2]. The structure of each subunit, shown in figure 1, is composed of two transmembrane domains. These transmembrane domains are guarded by a large extracellular loop and two intracellular N- and C-termini [3].In addition there is a fourth ??-subunit, which share sequential similarity with the ??- subunit and can form a functional ion-channel together with the ??- and ??-subunits. All these subunits are essential for transport of functional channels on the membrane [4]. These four subunits are essential for the composition of functional hetrotetramers. The kidney ENaC is a heterotramer of 2??1??1??. The stabilization of ENaC channel occur by the regulation of Ion flux. The ion flux is regulated by changes in ENaC gene transcription and phosphatidylinositides influenced by aldosterone, vasopressin and glucocorticoid. The genes which encode four subunits of ENaC are SCNN1A, SCNN1B, SCNN1G, SCNN1D [5] and their four related amiloride sensitive Na channels are, ACCN1, ACCN2, ACCN3, ACCN4, respectively. Epithelial Na+ transport control homeostasis of body fluid content influencing blood pressure. The rate-limiting step of the epithelial Na+ transport is the entry step of Na+ across the apical membrane via ENaC. ENaC activity is regulated by PKA, PTK (RTK), and PKN [6] and these regulatory pathways can be seen in Figure 2.The epithelial Na+ transport is activated by hypotonic stress by stimulating translocation of ENaC to the apical membrane from the intracellular store site. The ENAc translocation is stimulated by activation of RTK mediated by a change in membrane tension and/or a change in cytosolic Cl’ concentration without any ligand binding to RTK-involved receptors[7]. These changes in the activity and localization of ENaC control the blood pressure and homeostasis of our body environments. The blood pressure depends on body fluid volume regulated by amounts of Na+ reabsorption across epithelial cells in principle cells of collecting ducts of the kidney [8-11]. This amount of ENaC-mediated Na+ transport can be determined at the apical membrane by, (1) the number of ENaCs; (2) individual ENaC activity; (3) ENaC’s single channel conductance, and, (4) driving force for the Na+ entry via ENaCs across the apical membrane. The rate-limiting step occurs in the aldosterone-sensitive distal nephron (ASDN) [12] which includes DCT2, connecting tubule and collecting duct (CD) [12]. This regulation of Na+ and fluid absorption is controlled by renin’angiotensin’aldosterone system (RAAS) and vasopressin (ADH). The inactivation of ENaC in the distal part of the nephron shows no requirement for regulation of Na+ & K+ reabsorption [13]. In contrast to inactivation of ENaC in the distal part, the more proximal inactivation showed the cortical connecting tubule as relevant site of aldosterone-mediated sodium reabsorption 1[14] Components of the (RAAS) exist in kidney can generate angiotensin II (ANG II). CD-derived renin follows two action pathways. (1) By direct action on intercalated cells through prorenin receptors [15]; (2) By cleavage of angiotensinogen for angiotensin II and activate AT1R production [16]. Renin increases distal nephron salt reabsorption and thereby increases blood pressure. The CD-produced renin in addition to angiotensin-II modulates BP. This effect seems to be associated with changes in ENaC expression [17]. ATRAP deficiency exacerbated angiotensin-II-mediated hypertension by pathological activation of renal tubular AT1R. This directly stimulates ENaC in the distal tubules and enhances sodium retention in an aldosterone- independent manner [18].
Hypertension affects 25% of adult population in the world[19]. There are no symptoms for hypertension and its prolonged prevalence cause damage to blood vessels and increase the risk of heart attack and stroke. The mutation in ENaC are linked to genetic disorders causing hypertension. Maximal ENaC channel activity is obtained by the expression of all alpha, beta, gamma subunits. Therefore the expression of singular subunit or some of their combinations like ‘?, or ‘?, results in low or moderate ENaC activity [2]. This can be seen in PHAI where loss of function of mutations in either of ??, ??, or ?? ENaC causes this PHAI disease [20,21]. In PHAI all of the subunits and their combination exhibit reduced levels of ENaC expression and its activity [2,22]. In contrast to the ENaC loss of function mutations causing PHAI, the gain of these function mutations in the ENaC channel causes
Liddle syndrome.
Liddlesyndrome is an auto somal dominant disease leading to early onset of hypertension. It is caused by mutations in the epithelial Na+ channel (ENaC). Several deletions/mutations have been identified that cause Liddle syndrome, all map to ?? or ?? ENaC and lead to elevated channel numbers and activity at the plasma membrane. These genetic defects causes deletion of the C-terminus of ?? ENaC or ?? ENaC [23,24], or mutate a proline or a tyrosine within a short sequence, called the PY motif [25,26,27,28]. The PY motif serves as a binding site for the Nedd4 family of ubiquitin ligases [29] The mutated region, called the PY (Pro-Pro-x-Tyr) motif acts as a binding site for Nedd4-2. Nedd4-2 is an E3 ubiquitin ligase. Nedd4-2 and ENaC ubiquitylation regulate the number of cleaved channels at the plasma membrane. Nedd4-2 binds the ENaC PY motif via its WW domains. Normally this binding of Nedd4-2 with ENaC processes ENaC ubiquitylation and endocytosis causes the reduction of the number of active channels at the plasma membrane and limits the ENaC cell surface expression and its activity, as shown by figure 3.
The ubiquitylation plays an important role in the control of Na+ homeostasis. The process of ubiquitylation can be reversed by the action of DUBs. DUBs are deubliquating enzymes. With respect to renal Na+ transport, ubiquitin-protein ligase NEDD4-2 ubiquitylates posttranslational modification comprising ubiquitin, either ENaC or NCC and negatively controls the functional expression and activity at the plasma membrane [30,31]. SGK1 phosphorylates NEDD4-2, creating binding sites for 14-3-3??, and interfering with the interaction of NEDD4-2 with ENaC [32,33,34]. The importance of this mechanism in the regulation of ENaC and NCC is documented by Liddle’s syndrome, in which mutations in the genes encoding the ?? and ??ENaC subunit lead to the inactivation of binding motifs for the ubiquitin-protein ligase NEDD4-2, leading to increased retention of mutant ENaC at the cell surface and to elevated channel activity [35,36,37]. This ubiquitylation of ENaC by the impairment of Nedd4-2 has been shown in Figure 4. Moreover, channel feedback inhibition by elevated intracellular Na+ concentrations exhibited by wild-type ENaC is defective in ENaC bearing the Liddle syndrome mutations in the PY motif, further exacerbating Na+ loading.This results in the accumulation of ENaC active channels at the cell surface and increased Na+ absorption in the distal nephron. This causes elevation in blood volume and blood pressure. This gives the authentication of Liddle syndrome. Small molecules causing destabilization of cell surface ENaC and increased Nedd4-2 activity in the kidney can increase hypertension. In addition to aldosterone, the hormone vasopressin also increases ENaC activity and water absorption in the distal nephron causing increased body fluid level.
Liddle syndrome patients are treated with the inhibitors amiloride or triamterene, which are ENaC antagonists. In addition to these blocker they are put on low salt diet for the stabilization of hypertension. Liddle syndrome is a rare disorder and is very similar to other forms of hypertension. The other forms of hypertension have no identified genetic components and this could be treated by the inhibition of the ENaC activity. The rate limiting step controlling Na+ and fluid reabsorption in the nephron is provides an attractive target for the treatment of hypertension. A high throughput assay has been developed that allows quantification of the amounts of cell surface ENaC. The key role played by ubiquitin system/Nedd4-2 in regulation of ENaC cell surface stability and ENaC function, causes stabilized/increased ENaC levels. Therefore identification of compounds that destabilizes/decreases ENaC levels at plasma membrane can provide potential therapeutic benefits for the treatment of hypertension. Stimulation of Nedd4-2 activity targeted specifically to ENaC in kidney causing endocytosis or degradation of ENaC activity could also prove effective towards hypertension but this will have no affect on Liddle syndrome, since it inhibit ENaC internalisation and insensitive to Nedd4-2 [38].

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