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Nephrotic syndrome, especially the steroid-resistant form, is often complicated by hypertension in childhood. The syndrome is common in black children. However, the histopathological finding of membranous nephropathy in children with nephrotic syndrome is rare. Liddle's syndrome is a rare genetic abnormality that presents with salt-sensitive hypertension caused by constitutive activation of the amiloride-sensitive epithelial sodium channel. The epithelial sodium channel comprises homologous a, ß, and? subunits that share similar structures. Gene mutations associated with Liddle's syndrome occur in either the ß or? subunits and disturb or truncate a conserved proline-rich sequence (i.e., PY motif), leading to constitutive activation of the epithelial sodium channel. The association of nephrotic syndrome with Liddle's syndrome has only been described in an adult patient. We present here the first case of these two syndromes (nephrotic syndrome and Liddle's-like syndrome) co-existing in a child with membranous nephropathy in his histopathological finding on kidney biopsy. [ABSTRACT FROM AUTHOR]

The association of the cystic fibrosis transmembrane conductance regulator (CFTR) and epithelial sodium channel (ENaC) in the pathophysiology of cystic fibrosis (CF) is controversial. Previously, we demonstrated a close physical association between wild-type (WT) CFTR and WT ENaC. We have also shown that the F508del CFTR fails to associate with ENaC unless the mutant protein is rescued pharmacologically or by low temperature. In this study, we present the evidence for a direct physical association between WT CFTR and ENaC subunits carrying Liddle's syndrome mutations. We show that all three ENaC subunits bearing Liddle's syndrome mutations (both point mutations and the complete truncation of the carboxy terminus), could be coimmunoprecipitated with WT CFTR. The biochemical studies were complemented by fluorescence lifetime imaging microscopy (FLIM), a distance-dependent approach that monitors protein-protein interactions between fluorescently labeled molecules. Our measurements revealed significantly increased fluorescence resonance energy transfer between CFTR and all tested ENaC combinations as compared with controls (ECFP and EYFP cotransfected cells). Our findings are consistent with the notion that CFTR and ENaC are within reach of each other even in the setting of Liddle's syndrome mutations, suggestive of a direct intermolecular interaction between these two proteins. [ABSTRACT FROM AUTHOR]

Benjamin T Enslow1, James D Stockand1, Jonathan M Berman2 1UT Health, San Antonio, TX, USA; 2New York Institute of Technology College of Osteopathic Medicine at Arkansas State University, Jonesboro, AR, USACorrspondence: Jonathan M BermanNew York Institute of Technology at Arkansas State University, Jonesboro, AR 72467, USATel +1 870 680 8896Email jberma03@nyit.eduAbstract: Liddle’s syndrome is a genetic disorder characterized by hypertension with hypokalemic metabolic alkalosis, hyporeninemia and suppressed aldosterone secretion that often appears early in life. It results from inappropriately elevated sodium reabsorption in the distal nephron. Liddle’s syndrome is caused by mutations to subunits of the Epithelial Sodium Channel (ENaC). Among other mechanisms, such mutations typically prevent ubiquitination of these subunits, slowing the rate at which they are internalized from the membrane, resulting in an elevation of channel activity. A minority of Liddle’s syndrome mutations, though, result in a complementary effect that also elevates activity by increasing the probability that ENaC channels within the membrane are open. Potassium-sparing diuretics such as amiloride and triamterene reduce ENaC activity, and in combination with a reduced sodium diet can restore normotension and electrolyte imbalance in Liddle’s syndrome patients and animal models. Liddle’s syndrome can be diagnosed clinically by phenotype and confirmed through genetic testing. This review examines the clinical features of Liddle’s syndrome, the differential diagnosis of Liddle’s syndrome and differentiation from other genetic diseases with similar phenotype, and what is currently known about the population-level prevalence of Liddle’s syndrome. This review gives special focus to the molecular mechanisms of Liddle’s syndrome.Keywords: ENaC, Liddle’s syndrome, hypertension, blood pressure, distal nephron

Abstract Background Liddle’s syndrome is a rare monogenic form of hypertension caused by truncating or missense mutations in the C termini of the epithelial sodium channel (ENaC) β or γ subunits. Patients with this syndrome present with early onset of hypertension, hypokalemia, metabolic alkalosis, hyporeninemia and hypoaldosteronism, and a potassium-sparing diuretics (triamterene or amiloride) can drastically improves the disease condition. Although elderly patients having these characteristics were considered to have Liddle’s syndrome or Liddle’s-like syndrome, no previous report has indicated that Liddle’s-like syndrome could be caused by nephrotic syndrome of primary glomerular disease, which is characterized by urinary excretion of > 3 g of protein/day plus edema and hypoalbuminemia, or has explained how the activity function of ENaC could be affected in the setting of high proteinuria. Case presentation A 65-year-old Japanese man presented with nephrotic syndrome. He had no remarkable family history, but had a medical history of hypertension and hyperlipidemia. On admission, hypertension, spironolactone-resistant hypokalemia (2.43 mEq/l), hyporeninemic hypoaldosteronism, and metabolic alkalosis, which suggested Liddle’s syndrome, were observed. Treatment with triamterene together with a steroid for nephrotic syndrome resulted in rapid and remarkable effective on improvements of hypertension, hypokalemia, and edema of the lower extremities. Renal biopsy revealed membranous nephropathy (MN) as the cause of nephrotic syndrome, and advanced gastric cancer was identified on screening examination for cancers that could be associated with the development of MN. After total gastrectomy, triamterene was not required and proteinuria decreased. A mutation in the β or γ subunits of the ENaC gene was not identified. Conclusion We reported for the first time a case of Liddle’s-like syndrome associated with nephrotic syndrome secondary to MN. Aberrant activation of ENaC was suggested transient during the period of high proteinuria, and the activation was reversible with a decrease in proteinuria.

A 19-year-old male with early refractory hypertension, hypokalemia, serum potassium level of 3.4 mmol/l and hypoaldosteronemia was indicated in the present study. According to the results of laboratory tests and examinations, the patient was suspected of having Liddle's syndrome (LS). Genetic analysis of SCNN1B revealed a deletion mutation (c.1721delC). This mutation caused a length extension of SCNN1B coding sequence, which resulted in p.Pro574HisfsX675. A total of 34 family members were enrolled in the study and 29 of these family members underwent genetic testing. A total of 10 family members were clinically diagnosed with hypertension. Notably, 5 family members shared the same gene mutation as the proband and all cases with the mutation had hypertension. Blood pressure of the gene mutation carriers was well controlled by tailored treatment. In conclusion, a patient with early onset and refractory hypertension, hypokalemia and hypoaldosteronemia was diagnosed clinically and genetically with LS. Notably, a novel mutation (c.1721delC) was identified by DNA analysis. The present findings indicate that genetic analysis is useful, not only in the diagnosis of LS, but also in designing a tailored treatment. [ABSTRACT FROM AUTHOR]

Liddle's syndrome, an autosomal dominant form of monogenic hypertension, is characterized by salt-sensitive hypertension with early penetrance, hypokalemia, metabolic alkalosis, suppression of plasma rennin activity and aldosterone secretion, and a clear-cut response to epithelial sodium channel blockers but not spironolactone therapy. Here, we describe the case of a 16-year-old boy patient with resistant hypertension (maintain 170–180/100–110 mm Hg after administration four kinds of antiypertensive drugs) and severe hypokalemia. After a series of checks, we exclude primary aldosteronism and renal artery stenosis and other diseases. Finally, the Liddle syndrome was diagnosed because of the DNA sequencing found that the proband's mother and himself had mutations P616L (c.1847 C>T) in the SCNN1B gene. Liddle syndrome should be considered as a cause of hypertension in children or adolescents particularly with suppressed renin activity. Early diagnosis and appropriately tailored treatment avoid complications of long-term unrecognized or inappropriately managed hypertension. Genetic testing has made it possible to make accurate diagnoses and develop tailored therapies for mutation carriers. The role of genetic testing and genetic counseling in establishing the early diagnosis of Liddle's syndrome is important. [ABSTRACT FROM AUTHOR]

Serine proteases, both soluble and cell-attached, can activate the epithelial sodium channel (ENaC) proteolytically through release of a putative 43-mer inhibitory tract from the ectodomain of the γ-subunit. ENaC controls renal Na excretion and loss-of-function mutations lead to low blood pressure, while gain-of-function mutations lead to impaired Na excretion, hypertension, and hypokalemia. We review an emerging pathophysiological concept that aberrant glomerular filtration of plasma proteases, e.g., plasmin, prostasin, and kallikrein, contributes to proteolytic activation of ENaC, both in acute conditions with proteinuria, like nephrotic syndrome and preeclampsia, and in chronic diseases, such as diabetes with microalbuminuria. A vast literature on renin-angiotensin-aldosterone system and volume homeostasis from the last four decades show a number of common characteristics for conditions with albuminuria compatible with impaired renal Na excretion: hypertension and volume retention is secondary to proteinuria in, e.g., preeclampsia and nephrotic syndrome; plasma concentrations of renin, angiotensin II, and aldosterone are frequently suppressed in proteinuric conditions, e.g., preeclampsia and diabetic nephropathy; blood pressure is salt-sensitive in conditions with microalbuminuria/proteinuria; and extracellular volume is expanded, plasma atrial natriuretic peptide (ANP) concentration is increased, and diuretics, like amiloride and spironolactone, are effective blood pressure-reducing add-ons. Active plasmin in urine has been demonstrated in diabetes, preeclampsia, and nephrosis. Urine from these patients activates, plasmin-dependently, amiloride-sensitive inward current in vitro. The concept predicts that patients with albuminuria may benefit particularly from reduced salt intake with RAS blockers; that distally acting diuretics, in particular amiloride, are warranted in low-renin/albuminuric conditions; and that urine serine proteases and their activators may be pharmacological targets. [ABSTRACT FROM AUTHOR]

Hypertension or an elevated blood pressure continues to be a major risk factor for cardiovascular disease. Despite intensive public education including lifestyle modification programs and the availability of safe and effective pharmacologic agents to treat hypertension, the treatment and control of hypertension is suboptimal. Over the past several decades, there have been tremendous advances in the use of genetics to prevent, detect, and treat human disease states. Despite these advances and an intensive effort, the application of genetics to the broad population with hypertension has not met expectations. This review will address our present understanding and use of genetics in hypertension and areas where genetics may impact significantly our approach and clinical treatment of hypertension in the future. [ABSTRACT FROM AUTHOR]

Liddle's syndrome, an autosomal dominant form of monogenic hypertension, is characterized by salt-sensitive hypertension with early penetrance, hypokalemia, metabolic alkalosis, suppression of plasma rennin activity and aldosterone secretion, and a clear-cut response to epithelial sodium channel (ENaC) blockers but not spironolactone therapy. Our understanding of ENaCs and Na+ transport defects has expanded greatly over the past two decades and provides detailed insight into the molecular basis of Liddle's syndrome. In this review, we offer an overview of recent advances in understanding the molecular genetics of Liddle's syndrome, involving mutation analysis, molecular mechanisms and genetic testing. The ENaC in the distal nephron is composed of α, β and γ subunits that share similar structures. Mutations associated with Liddle's syndrome are positioned in either β or γ subunits and disturb or truncate a conserved proline-rich sequence (i.e., PY motif), leading to constitutive activation of the ENaC. Genetic testing has made it possible to make accurate diagnoses and develop tailored therapies for mutation carriers. [ABSTRACT FROM AUTHOR]

Advances in genetic mapping and sequencing techniques have led to substantial progress in the study of rare monogenic (Mendelian) forms of abnormal blood pressure. Many disease-defining pathways for hypertension have been identified in the past two decades. Perturbations in renal salt handling appear to be a common mechanism underlying these rare syndromes of hypertension. Excess activation at various points in the mineralocorticoid signaling pathway and malfunctioning of the autonomic (specifically sympathetic) nervous system have both been implicated in inducing hypertension, while complementary studies examining low blood pressure phenotypes have identified novel pathways exclusively linked to renal salt wasting in either the thick ascending limb or the distal nephron. The genetic defects and the physiological and cellular pathways affected in these various disorders are reviewed here. Importantly, studies have suggested that genetic variation affecting these same genes and pathways may play an important role in explaining the variation of blood pressure levels in the general population. The investigation of rare syndromes of human blood pressure variation has important implications for improving the diagnosis and treatment of hypertension. [ABSTRACT FROM AUTHOR]

BackgroundLiddle's syndrome (LS) is a monogenic form of hypertension simulating a mineralocorticoid excess, and is currently suspected in young hypokalemic hypertensives. The aims of the study were: (i) to evaluate the clinical phenotype of LS in a newly identified Italian family of Sicilian origin carrying a gain-of-function mutation of the β subunit of the epithelial sodium channel (ENaC) (P617L) previously reported by our group in an apparently unrelated Sicilian patient presenting the typical phenotype of LS including hypokalemia; (ii) to determine whether an unknown biological relationship exists between the newly identified family and the family of the proband previously reported.MethodsGenetic analysis was performed in the present family, in the individual in which the βP617L mutation was first observed, and in his relatives.ResultsβP617L mutation was identified in the proband and in three maternal relatives. None of them showed hypokalemia. Mild to severe early onset hypertension and left ventricular hypertrophy were present in all of them. Analysis of mitochondrial DNA (mtDNA) and Y chromosome profiles in the present family and in the proband's family previously reported showed the absence of a relationship between them. The availability of only one carrier of the mutation in one of the two families meant that a genetic analysis able to assess a founder effect was not feasible.ConclusionsLS should be considered in all cases of early onset hypertension, independently of the plasma potassium concentration. The incidence of LS may be greater than is currently thought, because hypokalemia is not invariably present.American Journal of Hypertension (2011). doi:10.1038/ajh.2011.76 [ABSTRACT FROM AUTHOR]

Abstract: Studies aiming at the elucidation of the genetic basis of rare monogenic forms of hypertension have identified mutations in genes coding for the epithelial sodium channel ENaC, for the mineralocorticoid receptor, or for enzymes crucial for the synthesis of aldosterone. These genetic studies clearly demonstrate the importance of the regulation of Na+ absorption in the aldosterone-sensitive distal nephron (ASDN), for the maintenance of the extracellular fluid volume and blood pressure. Recent studies aiming at a better understanding of the cellular and molecular basis of ENaC-mediated Na+ absorption in the distal part of nephron, have essentially focused on the regulation ENaC activity and on the aldosterone-signaling cascade. ENaC is a constitutively open channel, and factors controlling the number of active channels at the cell surface are likely to have profound effects on Na+ absorption in the ASDN, and in the amount of Na+ that is excreted in the final urine. A number of membrane-bound proteases, kinases, have recently been identified that increase ENaC activity at the cell surface in heterologous expressions systems. Ubiquitylation is a general process that regulates the stability of a variety of target proteins that include ENaC. Recently, deubiquitylating enzymes have been shown to increase ENaC activity in heterologous expressions systems. These regulatory mechanisms are likely to be nephron specific, since in vivo studies indicate that the adaptation of the renal excretion of Na+ in response to Na+ diet occurs predominantly in the early part (the connecting tubule) of the ASDN. An important work is presently done to determine in vivo the physiological relevance of these cellular and molecular mechanisms in regulation of ENaC activity. The contribution of the protease-dependent ENaC regulation in mediating Na+ absorption in the ASDN is still not clearly understood. The signaling pathway that involves ubiquitylation of ENaC does not seem to be absolutely required for the aldosterone-mediated control of ENaC. These in vivo physiological studies presently constitute a major challenge for our understanding of the regulation of ENaC to maintain the Na+ balance. [Copyright &y& Elsevier]

The knowledge of the genetic bases of hypertension has improved over the last decade; this area of research has high priority due to the high incidence of hypertension and its impact on public health. Monogenetic mineralocorticoid hypertension syndromes are associated with suppressed plasma renin activity due to excessive activation of the mineralocorticoid pathway. We review the pathophysiology, phenotype, and method of diagnosis for familial hyperaldosteronism type I and type II, hypertensive forms of congenital adrenal hyperplasia, 11β-hydroxysteroid dehydrogenase type 2 deficiency, Liddle’s syndrome, an activating mutation of the MR, and glucocorticoid resistance. We also review some genes that could contribute to essential hypertension. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The article discusses the case of a Thai family who presented with Liddle's syndrome caused by a novel P615H missense mutation in the proline-rich domain of the SCNN1B gene coding for the beta-subunit of epithelial sodium channel (ENaC) gene. Several effects of the missense or frameshift mutations in the ENaC gene include excessive salt and water resorption from the distal nephron, volume expansion and suppression of plasma renin activity and serum aldosterone secretion. Information about the Liddle's syndrome is presented.

Monogenic mutations leading to excessive activation of the mineralocorticoid pathway result, almost always, in suppressed renin and hypertension in adult life and sometimes in hypokalaemia and alkalosis, which can be severe. In most of these syndromes, precise molecular changes in specific steroidogenic or effector genes have been identified, permitting appreciation of (1) pathophysiology, (2) great diversity of phenotype and (3) possibility of genetic methods of diagnosis. Yet to be achieved elucidation of the genetic basis of familial hyperaldosteronism type II, the most common and clinically significant of them, will enhance detection of primary aldosteronism, currently the commonest specifically treatable and potentially curable form of hypertension. While classic, complete-phenotype presentations of monogenic forms of mineralocorticoid hypertension are rarely recognised, more subtle genetic expression causing less florid manifestations could represent a significant proportion of so-called ‘essential hypertension.’ [Copyright &y& Elsevier]

Activity of the epithelial Na+ channel (ENaC) is limiting for Na+ reabsorption at the distal nephron. Gain-of-function mutations in ENaC cause Liddle's syndrome: a severe form of inheritable hypertension. Several polymorphisms in α-hENaC possibly associated with abnormal Na+ handling by the kidney and the salt-sensitive hypertension prevalent in black populations have been reported. The functional effects of α-hENaC polymorphisms on channel activity, however, remain controversial and have not been directly tested in a mammalian background. We ask here whether polymorphisms at positions 334, 618, and 663 in α-hENaC influence channel activity. Activity of wild-type (A334, C618, A663) and polymorphic ENaC expressed in Chinese hamster ovary cells was assessed with patch-clamp electrophysiology. While the A334T polymorphism had little effect on macroscopic ENaC currents, the C618F and A663T polymorphisms significantly increased ENaC activity >3.3- and 1.6-fold, respectively. Similarly, polymorphic ENaC had greater activity compared with wild-type channels in excised patches with activity of C618F and A663T channels increased 3.8- and 2.6-fold, respectively. Unitary channel conductances and reversal potentials were not different for polymorphic and wild-type ENaC. Increases in activity resulted primarily from increases in the apparent number of active (polymorphic) channels in the plasma membrane. Moreover, addition of a reducing agent to the cytosol significantly increased activity of wild-type ENaC equal to that of C618F polymorphic channels but had no effect on these latter channels. These results are consistent with the C618F and A663T polymorphisms leading to elevated ENaC activity with the possibility that they facilitate altered Na+ handling by the kidney. [ABSTRACT FROM AUTHOR]

Regulation of the epithelial sodium channel (ENaC) is important for the long-term control of arterial blood pressure as evidenced by gain of function mutations of ENaC causing Liddle’s syndrome, a rare form of hereditary arterial hypertension. In Xenopus laevis oocytes expressing ENaC a spontaneous decline of ENaC currents over time, so-called rundown, is commonly observed. Mechanisms involved in rundown may be physiologically relevant and may be related to feedback regulation of ENaC by intra- or extracellular Na+. We tested the effect of extracellular Na+ removal on ENaC rundown. Spontaneous rundown of ENaC was largely prevented by extracellular Na+ removal and was partially prevented by primaquine suggesting that it is due to endocytic channel retrieval. Liddle’s syndrome mutation caused a reduced rate of rundown, and in oocytes expressing the mutated channel extracellular Na+ removal not only prevented rundown but even increased the ENaC currents (runup). Acute exposure to high extracellular Na+ drastically reduced whole-cell currents and surface expression of wild-type ENaC, while these effects were much smaller in ENaC with Liddle’s syndrome mutation consistent with a stabilization of the mutated channel in the plasma membrane. Interestingly, the apparent intracellular Na+ concentration [Na+]i-app was high (>60 mM) in ENaC-expressing oocytes but rundown was not associated with a further increase in [Na+]i-app. We conclude that the inhibitory effect of extracellular Na+ removal on rundown is due to an inhibition of endocytic ENaC retrieval. [ABSTRACT FROM AUTHOR]

Pseudohyperaldosteronism is characterized by a clinical picture of hyperaldosteronism with suppression of plasma renin activity and aldosterone. Pseudohyperaldosteronism can be due to a direct mineralocorticoid effect, as with desoxycorticosterone, fluorohydrocortisone, fluoroprednisolone, estrogens, and the ingestion of high amounts of glycyrrhetinic acid. A block of 11β-hydroxysteroid-dehydrogenase type 2 (11HSD2), the enzyme that converts cortisol into cortisone, at the level of epithelial target tissues of aldosterone, is involved in other cases. This mechanism is related either to a mutation of the gene, which encodes 11HSD2 (apparent mineralocorticoid excess syndrome and some cases of low renin hypertension) or to an acquired reduction of the activity of the enzyme due to glycyrrhetinic acid, carbenoxolone, and grapefruit juice. In other cases saturation of 11HSD2 may be involved as in severe Cushing's syndrome and chronic therapy with some corticosteroids. Recently, an activating mutation of the mineralocorticoid receptor gene has been described. Another genetic cause of pseudohyperaldosteronism is the syndrome of Liddle, which is due to a mutation of the gene encoding for β and γ subunits of the sodium channels. [ABSTRACT FROM AUTHOR]

Focuses on those transgenic models that have had an impact on the understanding of the physiology and pathophysiology of renal tubular function. Technique used for examining gene expression in renal tubular cells; Methodology used for describing gene targeting technology; Information on the gene targeting experiments of the renin-angiotensin system.

Liddle's syndrome is a rare form of autosomal-dominant salt-sensitive hypertension. Constitutive activation of the amiloride-sensitive distal renal epithelial sodium channel (ENaC) is essential for salt-sensitive hypertension. Recently, several DNA analysis studies have indicated that there is a mutation of C-terminus of either the β γ subunit. We sequenced the C-termini of the β and γ subunits of the ENaC in a Japanese family with hypertension and hypopotassemia without excess minerarocorticoids, clinically diagnosed as Liddle's syndrome. The mutation of the ENaC of this family was β R564X. Since such case seem to be rare in the literature, detailed data are shown in this report. [ABSTRACT FROM AUTHOR]

Presents a case of an aged female schoolteacher who was referred for the evaluation of arterial hypertension. Medical history of the patient; Findings from clinical examinations; Discussion on monogenic hypertension.

Dysfunction of epithelial sodium transport: From human to mouse. The highly amiloride-sensitive epithelial sodium channel (ENaC) is an apical membrane constituent of cells of many salt-absorbing epithelia. In the kidney, the functional relevance of ENaC expression has been well established. ENaC mediates the aldosterone-dependent sodium reabsorption in the distal nephron and is involved in the regulation of blood pressure. Mutations in genes encoding ENaC subunits are causative for two human inherited diseases: Liddle's syndrome, a severe form of hypertension associated with ENaC hyperfunction, and pseudohypoaldosteronism (PHA-1), a salt-wasting syndrome caused by decreased ENaC function. Transgenic mouse technologies provide a useful tool to study the role of ENaC in vivo. Different mouse lines have been established in which each of the ENaC subunits was affected. The phenotypes observed in these mice demonstrated that each subunit is essential for survival and for regulation of sodium transport in kidney and colon. Moreover, the α subunit plays a specific role in the control of fluid absorption in the airways at birth. Such mice can now be used to study the role of ENaC in various organs and can serve as models to understand the pathophysiology of these human diseases. [ABSTRACT FROM AUTHOR]

Regulation of the endothelial Na+ channel by Nedd4 and by ubiquitination. The epithelial Na+ channel (ENaC) is comprised of three subunits, α, β and γ, and plays an essential role in Na+ and fluid absorption in the kidney, colon and lung. We had identified proline-rich sequences at the C termini of αβγENaC, which include the sequence PPxY, the PY motif. This sequence in β or γENaC is deleted or mutated in Liddle's syndrome, a hereditary form of arterial hypertension. Our previous work demonstrated that these PY motifs bind to the WW domains of Nedd4, a ubiquitin protein ligase containing a C2 domain, three or four WW domains and a ubiquitin protein ligase Hect domain. Accordingly, we have recently demonstrated that Nedd4 regulates ENaC function by controlling the number of channels at the cell surface, that this regulation is impaired in ENaC bearing Liddle's syndrome mutations, and that ENaC stability and function are regulated by ubiquitination. The C2 domain is responsible for localizing Nedd4 to the plasma membrane in a Ca2+-dependent manner, and in polarized epithelial MDCK cells this localization is primarily apical. In accordance, electrophysiological characterization of ENaC expressed in MDCK cells revealed inhibition of channel activity by elevated intracellular Ca2+ levels. Thus, in response to Ca2+, Nedd4 may be mobilized to the apical membrane via its C2 domain, where it binds ENaC via Nedd4-WW:ENaC–PY motifs' interactions, leading to ubiquitination of the channel by the Nedd4-Hect domain and subsequent channel endocytosis and lysosomal degradation. This process may be at least partially impaired in Liddle's syndrome due to reduced Nedd4 binding, leading to increased retention of ENaC at the cell surface. [ABSTRACT FROM AUTHOR]

Provides insights into the regulation of extracellular volume and blood pressure in disorders of the epithelial sodium channel. Characterization of different types of pseudohypoaldosteronism (PHA); Molecular problems that might possibly lead to PHA; Molecular nature of the epithelial sodium channel.

Investigates the mechanism of distal nephron sodium transport. Demonstration of metabolic and clinical alterations; Mechanism of sodium reabsorption in the nephron; Effects of secondary transporter on heterogeneity of nephrons.