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Endocrine hypertension
Published in Philip E. Harris, Pierre-Marc G. Bouloux, Endocrinology in Clinical Practice, 2014
Frances McManus, John M. Connell, Marie Freel
Liddle’s syndrome is a rare, autosomal dominant condition and associated with moderate-to-severe hypertension presenting in childhood, arising from over activation of the epithelial sodium channel (ENaC). In common with PA, patients are hypokalemic with a metabolic alkalosis and have a low plasma renin, but in this case plasma aldosterone concentrations are low.30 The genetic abnormality lies on chromosome 16, and “gain-of-function mutations” identified to date lie in the cytoplasmic C-terminal tails of the β- and γ-subunits of ENaC.31 These mutations result in loss of an adaptor motif that interacts with neural precursor cell-expressed, developmentally down regulated 4-2 (Nedd4-2). Nedd4-2 ligates a ubiquitin “tag” to the ENaC that targets it for internalization and subsequent destruction. This induces constitutive activity of the ENaC in the cortical collecting duct, as if activated by aldosterone. Importantly, in this condition, spironolactone is not effective because activation of ENaC is not due to excessive aldosterone levels and is independent of the MR. However, the ENaC is amiloride sensitive, and this is the treatment of choice in these patients.
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.
Genetic screening of SCNN1B and SCNN1G genes in early-onset hypertensive patients helps to identify Liddle syndrome
Published in Clinical and Experimental Hypertension, 2018
Kun-Qi Yang, Chao-Xia Lu, Peng Fan, Ying Zhang, Xu Meng, Xue-Qi Dong, Fang Luo, Ya-Xin Liu, Hui-Min Zhang, Hai-Ying Wu, Jun Cai, Xue Zhang, Xian-Liang Zhou
In this study, we reported a recurrent missense mutation, c.1853C>A, p.P618H, in SCNN1B in a Chinese family and established the diagnosis of LS in the symptomatic members. ENaC resides in various epithelial tissues throughout the body, including the lung, exocrine glands, colon, and distal nephron (5). ENaC in the distal nephron is composed of homologous α, β, and γ subunits, encoded by SCNN1A, SCNN1B, and SCNN1G, respectively, which share a conserved proline-rich sequence, PPPXYXXL (named the PY motif), in the cytosolic C-terminus (6). The PY motif is implicated in the interaction between ENaC and Nedd4-2, a specific ubiquitin ligase, in which WW domains of Nedd4-2 bind to PY motifs in ENaC subunits, catalyzing the ubiquitination of ENaC and leading to its internalization and degradation (7,8).
Expression of NEDD4L and ENaC in Urinary Extracellular Vesicles in Pre-eclampsia
Published in Hypertension in Pregnancy, 2023
P.Y.M. Leung, M Katerelos, S. Choy, N Cook, M Lee, K Paizis, A Abboud, J. A. Manning, P.F Mount, D.A Power
In conclusion, ENaC expression is upregulated in UEV of pre-eclamptic subjects but this is not associated with changes in UEV full-length NEDD4L expression. Current understanding of the critical role of NEDD4–2/NEDD4L and regulation of ENaC have been derived from gene knockout studies in mice, genetic studies in Liddle’s syndrome, and single nucleotide polymorphisms in the Nedd4l gene on chromosome 18 associated with hypertension in humans (28). To our knowledge, this is the first study investigating the NEDD4L/ENaC relationship in pre-eclampsia and there may be unique differences in its regulation in this condition and pregnancy.