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International Journal of Molecular... Apr 2023Epithelial sodium channels (ENaC) are part of a complex network of interacting biochemical pathways and as such are involved in several disease states. Dependent on site... (Review)
Review
Epithelial sodium channels (ENaC) are part of a complex network of interacting biochemical pathways and as such are involved in several disease states. Dependent on site and type of mutation, gain- or loss-of-function generated symptoms occur which span from asymptomatic to life-threatening disorders such as Liddle syndrome, cystic fibrosis or generalized pseudohypoaldosteronism type 1. Variants of ENaC which are implicated in disease assist further understanding of their molecular mechanisms in order to create models for specific pharmacological targeting. Identification and characterization of ENaC modifiers not only furthers our basic understanding of how these regulatory processes interact, but also enables discovery of new therapeutic targets for the disease conditions caused by ENaC dysfunction. Numerous test compounds have revealed encouraging results in vitro and in animal models but less in clinical settings. The EMA- and FDA-designated orphan drug solnatide is currently being tested in phase 2 clinical trials in the setting of acute respiratory distress syndrome, and the NOX1/ NOX4 inhibitor setanaxib is undergoing clinical phase 2 and 3 trials for therapy of primary biliary cholangitis, liver stiffness, and carcinoma. The established ENaC blocker amiloride is mainly used as an add-on drug in the therapy of resistant hypertension and is being studied in ongoing clinical phase 3 and 4 trials for special applications. This review focuses on discussing some recent developments in the search for novel therapeutic agents.
Topics: Animals; Epithelial Sodium Channels; Hypertension; Liddle Syndrome; Pseudohypoaldosteronism; Amiloride
PubMed: 37175488
DOI: 10.3390/ijms24097775 -
Current Hypertension Reviews 2020Advances in molecular research techniques have enabled a new frontier in discerning the mechanisms responsible for monogenic diseases. In this review, we discuss the... (Review)
Review
Advances in molecular research techniques have enabled a new frontier in discerning the mechanisms responsible for monogenic diseases. In this review, we discuss the current research on the molecular pathways governing blood pressure disorders with a Mendelian inheritance pattern, each presenting with a unique pathophysiology. Glucocorticoid Remediable Aldosteronism (GRA) and Apparent Mineralocorticoid Excess (AME) are caused by mutations in regulatory enzymes that induce increased production of mineralocorticoids or inhibit degradation of glucocorticoids, respectively. Geller syndrome is due to a point mutation in the hormone responsive element of the promotor for the mineralocorticoid receptor, rendering the receptor susceptible to activation by progesterone, leading to hypertension during pregnancy. Pseudohypoaldosteronism type II (PHA-II), also known as Gordon's syndrome or familial hyperkalemic hypertension, is a more variable disorder typically characterized by hypertension, high plasma potassium and metabolic acidosis. Mutations in a variety of intracellular enzymes that lead to enhanced sodium reabsorption have been identified. In contrast, hypertension in Liddle's syndrome, which results from mutations in the Epithelial sodium Channel (ENaC), is associated with low plasma potassium and metabolic alkalosis. In Liddle's syndrome, truncation of one the ENaC protein subunits removes a binding site necessary protein for ubiquitination and degradation, thereby promoting accumulation along the apical membrane and enhanced sodium reabsorption. The myriad effects due to mutation in phosphodiesterase 3A (PDE3A) lead to severe hypertension underlying sodium-independent autosomal dominant hypertension with brachydactyly. How mutations in PDE3A result in the phenotypic features of this disorder are discussed. Understanding the pathologies of these monogenic hypertensive disorders may provide insight into the causes of the more prevalent essential hypertension and new avenues to unravel the complexities of blood pressure regulation.
Topics: Blood Pressure; Genetic Predisposition to Disease; Heredity; Humans; Hypertension; Inheritance Patterns; Mutation; Pedigree; Phenotype; Prognosis; Risk Factors
PubMed: 30963979
DOI: 10.2174/1573402115666190409115330 -
Cellular and Molecular Life Sciences :... Sep 2006Hyper- and hypokalemia may carry severe clinical consequences. Different regulatory mechanisms, including the kidney, exert a tight regulation of plasma potassium... (Review)
Review
Hyper- and hypokalemia may carry severe clinical consequences. Different regulatory mechanisms, including the kidney, exert a tight regulation of plasma potassium levels. The renal pathway of potassium handling begins in the proximal tubule followed by the fine-tuning of its secretion or absorption at the distal tubule, including the thick ascending limb of Henle's loop, the distal convoluted tubule and the cortical collecting duct. Genetic studies in recent years have clarified the role of specific tubular channels and transporters in the pathogenesis of unique hyper- and hypokalemic tubulopathies, some of them non-hypertensive (pseudohypoaldosteronism, Bartter and Gitelman syndromes) and others hypertensive by definition (including Liddle and Gordon syndromes). This article reviews the genetic and clinical spectrum of hypokalemic and hyperkalemic tubulopathies.
Topics: Animals; Bartter Syndrome; Humans; Hyperaldosteronism; Hyperkalemia; Hypertension; Hypokalemia; Infant; Infant, Newborn; Kidney Diseases; Kidney Tubules; Models, Biological; Mutation; Potassium; Receptors, Calcium-Sensing; Syndrome
PubMed: 16810456
DOI: 10.1007/s00018-006-6011-0 -
Current Opinion in Nephrology and... Mar 2015NEDD4-2 is an ubiquitin-protein ligase that was originally identified as an interactor of the epithelial Na+ channel (ENaC); this interaction is defective in Liddle's... (Review)
Review
PURPOSE OF REVIEW
NEDD4-2 is an ubiquitin-protein ligase that was originally identified as an interactor of the epithelial Na+ channel (ENaC); this interaction is defective in Liddle's syndrome, causing elevated ENaC activity and salt-sensitive hypertension. In this review we aim to highlight progress achieved in recent years demonstrating that NEDD4-2 is involved in the control of Na+ transporters that are different from ENaC, but which also play a role in salt-sensitive hypertension.
RECENT FINDINGS
It has been shown that NEDD4-2 interacts with ubiquitylates and negatively regulates the thiazide-sensitive NCC (Na+,Cl- -cotransporter), both in vitro and in vivo in inducible, nephron-specific Nedd4-2 knockout mice. Moreover, evidence has been provided that NEDD4-2 is also involved in the regulation of human NHE3 (Na+,H+-exchanger 3) and NKCC2 (Na+,K+,2Cl- -cotransporter 2).
SUMMARY
The emerging role of NEDD4-2 in the regulation of different Na+ transporters along the nephron and the identification of human polymorphisms in the NEDD4-2 gene (Nedd4L) related to salt-sensitive hypertension makes this ubiquitin-protein ligase an interesting target for the development of antihypertensive drugs.
Topics: Animals; Antihypertensive Agents; Endosomal Sorting Complexes Required for Transport; Epithelial Sodium Channels; Humans; Hypertension; Nedd4 Ubiquitin Protein Ligases; Sodium Chloride, Dietary; Sodium-Phosphate Cotransporter Proteins; Ubiquitin-Protein Ligases
PubMed: 25602517
DOI: 10.1097/MNH.0000000000000097 -
Indian Journal of Endocrinology and... Sep 2012Low renin hypertension is an important and often underdiagnosed cause of hypertension. It may be associated with high aldosterone levels as in Conn's syndrome or low...
Low renin hypertension is an important and often underdiagnosed cause of hypertension. It may be associated with high aldosterone levels as in Conn's syndrome or low aldosterone levels as in Liddle syndrome, and syndrome of apparent mineralocorticoid excess, glucocorticoid remediable hypertension etc. Some forms of essential hypertension are also associated with low renin levels. Hypokalemia may be an important finding in low renin hypertension. The aldosterone to renin ratio helps in correct diagnosis. The treatment varies with etiology hence an accurate diagnosis is essential. Aldosterone antagonists play an important role in medical management of some varieties of low renin hypertension.
PubMed: 23087856
DOI: 10.4103/2230-8210.100665 -
The American Journal of the Medical... Jul 2010The kidneys play a pivotal role in causing some forms of hypertension and probably a permissive role in most, if not all, forms of hypertension. This concept of the... (Review)
Review
The kidneys play a pivotal role in causing some forms of hypertension and probably a permissive role in most, if not all, forms of hypertension. This concept of the critical role of the kidneys has been postulated for many years but has been solidified by the molecular unraveling of several monogenic forms of hypertension such as Liddle's syndrome, apparent mineralocorticoid excess and glucocorticoid-remedial aldosteronism. These and other hypertensive disorders cause sodium retention through excess Na reabsorption in the distal nephron. Some disorders of salt wasting and relative hypotension such as Bartter's syndrome, Gitelman's syndrome and pseudohypoaldosteronism also localize to Na transport abnormalities in the distal nephron. Hypertensive in the general population may also result from subtle abnormalities in sodium balance resulting from alterations in the distal nephron.
Topics: Genetic Predisposition to Disease; Genetic Variation; Humans; Hypertension; Kidney; Kidney Diseases; Sodium; Water-Electrolyte Imbalance
PubMed: 20610969
DOI: 10.1097/MAJ.0b013e3181e590f0 -
BMC Biochemistry Nov 2007In a simplified view, members of the HECT E3 family have a modular structure consisting of the C-terminal HECT domain, which is catalytically involved in the attachment... (Review)
Review
In a simplified view, members of the HECT E3 family have a modular structure consisting of the C-terminal HECT domain, which is catalytically involved in the attachment of ubiquitin to substrate proteins, and N-terminal extensions of variable length and sequence that mediate the substrate specificity of the respective HECT E3. Although the physiologically relevant substrates of most HECT E3s have remained elusive, it is becoming increasingly clear that HECT E3s play an important role in sporadic and hereditary human diseases including cancer, cardiovascular (Liddle's syndrome) and neurological (Angelman syndrome) disorders, and/or in disease-relevant processes including bone homeostasis, immune response and retroviral budding. Thus, molecular approaches to target the activity of distinct HECT E3s, regulators thereof, and/or of HECT E3 substrates could prove valuable in the treatment of the respective diseases. Publication history: Republished from Current BioData's Targeted Proteins database (TPdb; http://www.targetedproteinsdb.com).
Topics: Animals; DNA-Binding Proteins; Disease; Humans; Ubiquitin-Conjugating Enzymes; Ubiquitin-Protein Ligase Complexes; Ubiquitin-Protein Ligases
PubMed: 18047743
DOI: 10.1186/1471-2091-8-S1-S6 -
Hormone Research 2009The 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... (Review)
Review
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, 11beta-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.
Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 2; 11-beta-Hydroxysteroid Dehydrogenases; Adrenal Hyperplasia, Congenital; Angiotensinogen; Drug Resistance; Epithelial Sodium Channels; Glucocorticoids; Humans; Hyperaldosteronism; Hypertension; Mineralocorticoid Excess Syndrome, Apparent; Peptidyl-Dipeptidase A; Phenotype; Receptor, Angiotensin, Type 1; Receptors, Mineralocorticoid; Syndrome
PubMed: 19339789
DOI: 10.1159/000208798 -
BioMed Research International 2016The ENaC/degenerin ion channel superfamily includes the amiloride-sensitive epithelial sodium channel (ENaC) and acid sensitive ionic channel (ASIC). ENaC is a... (Review)
Review
The ENaC/degenerin ion channel superfamily includes the amiloride-sensitive epithelial sodium channel (ENaC) and acid sensitive ionic channel (ASIC). ENaC is a multimeric ion channel formed by heteromultimeric membrane glycoproteins, which participate in a multitude of biological processes by mediating the transport of sodium (Na(+)) across epithelial tissues such as the kidney, lungs, bladder, and gut. Aberrant ENaC functions contribute to several human disease states including pseudohypoaldosteronism, Liddle syndrome, cystic fibrosis, and salt-sensitive hypertension. Increasing evidence suggests that ion channels not only regulate ion homeostasis and electric signaling in excitable cells but also play important roles in cancer cell behaviors such as proliferation, apoptosis, invasion, and migration. Indeed, ENaCs/ASICs had been reported to be associated with cancer characteristics. Given their cell surface localization and pharmacology, pharmacological strategies to target ENaC/ASIC family members may be promising cancer therapeutics.
Topics: Acid Sensing Ion Channels; Amiloride; Animals; Apoptosis; Cell Movement; Cell Proliferation; Epithelial Sodium Channels; Humans; Neoplasm Invasiveness; Neoplasms; Signal Transduction; Sodium
PubMed: 27403419
DOI: 10.1155/2016/2190216