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CHD Genetics Part II
Published in Mark C Houston, The Truth About Heart Disease, 2023
CYP4A11. In terms of salt sensitivity and resistant hypertension, one of the most important is CYP4A11 which relates to sodium and water reabsorption and the role of the epithelial sodium channel (ENaC) function in the kidney. These patients have avid reabsorption of sodium in the kidney tubules from the ENaC which increases the blood volume, blood pressure, and risk for CHD. This type of hypertension is best treated with the drug Amiloride, which blocks the ENaC and results in a diuresis of salt and water to lower the blood pressure. Some of these patients may need a short- or long-term treatment with another type of diuretic, Indapamide.
Gene Therapy and Small Molecules Used in the Treatment of Cystic Fibrosis
Published in Yashwant Pathak, Gene Delivery, 2022
Manish P. Patel, Uma G. Daryai, Mansi N. Athalye, Praful D. Bharadia, Jayvadan Patel
Since the CFTR gene mutation causes hyperactivation of the epithelial sodium channel (ENaC), the absorption of Na+ ions is enhanced and the lung airway mucus becomes dehydrated. Hence, the inhibition of ENaC expression could serve as a promising therapeutic approach for the treatment of cystic fibrosis. One method for the inhibiting the expression of ENaC-encoding genes (SCNN1A, SCNN1B, SCNN1G, and SCNN1D encoding α, β, γ, and δ ENaC subunits, respectively) involves the use of a single strand nucleic acid known as antisense oligonucleotide (ASO) (Almughem et al., 2020). When this oligonucleotide is hybridized to mRNA, RNase H is triggered to slice the hybridized mRNA. Targeting the α-subunit of ENaC in the respiratory organ, using ASO might inhibit the cationic channel activity (Almughem et al., 2020). Another study showed the possibility of using aerosolized ENaC antisense oligonucleotide containing wing modifications to inhibit ENaC mRNA in CF-like mice models (Hajj and Whitehead, 2017). This aerosolized ENaC antisense oligonucleotide helped to cure various cystic fibrosis symptoms, like airway hyper-responsiveness and inflammation (Crosby et al., 2017).
Cystic fibrosis (mucoviscidosis)
Published in Louis-Philippe Boulet, Applied Respiratory Pathophysiology, 2017
If, on the other hand, there is depletion of ASL, sodium absorption through ENaC will be inhibited and chloride will be secreted, mostly at the level of CFTR channels. This will secondarily generate passive sodium movement (electrochemical gradient) and more transcellular water movement onto the epithelial surface layer (osmotic gradient).
A novel nonsense mutation in the β-subunit of the epithelial sodium channel causing Liddle syndrome
Published in Blood Pressure, 2021
Štěpán Mareš, Jan Filipovský, Kateřina Vlková, Martin Pešta, Václava Černá, Jaroslav Hrabák, Jitka Mlíková Seidlerová, Otto Mayer
Liddle syndrome (LS) is a hereditary form of arterial hypertension. Its key clinical characteristics are early onset of hypertension, hypokalaemia and suppressed plasma renin and aldosterone levels. It is a monogenic form of hypertension with an autosomal dominant pattern of inheritance [1]. LS is caused by activating mutations of epithelial sodium channel (ENaC) which is mainly expressed in aldosterone-sensitive distal nephron (Figure 1). ENaC is responsible for reabsorption of sodium, maintaining body salt and water homeostasis. This channel is composed of three homologous subunits (α-, β-, γ-) encoded by the genes SCNN1A, SCNN1B and SCNN1G [2,3]. Each subunit consists of cytoplasmic amino acid and carboxyl termini, two transmembrane domains, and a large extracellular loop. Carboxyl terminus contains sites of interaction with other proteins and signal transduction molecules that regulate ENaC function. Within the C-terminus of all three subunits there is a highly conserved sequence of amino acids named “PY motif” – a proline rich sequence which is a binding site for ubiquitin-protein ligase NEDD4 [3,4]. NEDD4 mediates the internalisation and degradation of ENaC. In general, mutations causing Liddle syndrome result in increased activity of ENaC. Most of them cause disruption or loss of PY motif of β or γ subunits and therefore impaired channel degradation (Figure 2). Additional mechanism such as disruption of disulphide bridge in extracellular loop of α subunit leading to elevation of channel open probability has been described as well [5–7].
Epithelial sodium channel blockade and new β-ENaC polymorphisms among normotensive and hypertensive adult Nigerians
Published in Clinical and Experimental Hypertension, 2019
Simiat O. Elias, Olusoga A. Sofola, Smith I. Jaja
The final control of sodium reabsorption takes place in the distal renal tubules involving the participation of the amiloride-sensitive Epithelial Sodium Channels (ENaC) (1) hence controlling sodium balance, extracellular fluid volume and arterial blood pressure (2,3). The transporters involved in sodium reabsorption are localized to specific segments of the nephron which mediate the entry of sodium across the apical membrane. These transporters include the Na+/H+ exchanger of the proximal tubule, the Na+/K+/2Cl− co-transporter of the thick ascending limbs of Henle, the Na+:Cl− co-transporter (NCC) expressed exclusively at the distal convoluted tubule especially in the early DCT (DCT1) becoming less along the late distal tubule (DCT2); and the α -, β- and γ- subunits of the epithelial sodium channel (ENaC) expression increases gradually along DCT2 and is robust in the connecting tubule (CNT) and the collecting duct (CD) (4). This arrangement of the NCC and ENaC protein expression in DCT2 generates three distinctive segments: DCT1 where only NCC is expressed, DCT2 where NCC and ENaC are co-expressed, and CNT/CD where only ENaC is expressed (5). Although the bulk of reabsorption of sodium is carried out in the proximal tubule, the fine control of sodium reabsorption is carried out in the distal nephron and collecting duct. This location of ENaC makes it an important candidate gene for its involvement in blood pressure control; increases in the activity of ENaC results in increased extracellular fluid volume and blood pressure (6).
Regulatory network analysis of hypertension and hypotension microarray data from mouse model
Published in Clinical and Experimental Hypertension, 2018
Yanli Zhu, Jingming Zhuo, Chunmei Li, Qian Wang, Xuefei Liu, Lin Ye
In recent years, modern molecular biological research has provided great advances in the understanding of the pathogenesis of BPH and BPL. Dopamine, its receptor, and its signal transduction pathways have been shown to be closely linked to BPH (7). Proximal renal tubules can synthesize dopamine by reabsorption of filtered L-dopamine, and LAT2 participates in the process of L-dopamine transportation (8). Furthermore, a serine/threonine kinase encoded by STK39, regulated by the Na+/Cl cotransporter NCCT, and further targeted by upstream WNK kinases has been associated with sodium-sensitive HTN (9). Another important gene, ATP2B1, was also shown to regulate intracellular calcium concentrations and balance vascular contractility, playing an important role in blood pressure regulation (10). In addition, NEDD4L encodes a protein that is the main ubiquitinase of ENaC (11). ENaC is regarded as a rate-limiting step for Na+ reabsorption and plays a crucial role in blood pressure regulation (12). Although these findings have laid the foundation for BPH research, there is still dearth of systematic studies for BPH treatment.