Ubiquitylation and the pathogenesis of hypertension

Ellison, David H.

doi:10.1172/jci66882

Cited by 11 publications

(13 citation statements)

References 20 publications

(27 reference statements)

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“…Accumulation of intracellular bENaC and gENaC was observed in the same model under dietary Na + loading, 20 and it was suggested by an accompanying editorial by Ellison that NEDD4-2 may not control directly the cell surface expression, but intracellular degradation. 55 Our data support such a model. Additionally, they suggest that under chronic K + depletion, NEDD4-2-dependent regulation of ENaC may act independently of factors that regulate its proteolytic cleavage.…”

Section: Discussionsupporting

confidence: 72%

Renal Tubular Ubiquitin-Protein Ligase NEDD4-2 Is Required for Renal Adaptation during Long-Term Potassium Depletion

Al‐Qusairi

Basquin

Roy

et al. 2017

JASN

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Adaptation of the organism to potassium (K) deficiency requires precise coordination among organs involved in K homeostasis, including muscle, liver, and kidney. How the latter performs functional and molecular changes to ensure K retention is not well understood. Here, we investigated the role of ubiquitin-protein ligase NEDD4-2, which negatively regulates the epithelial sodium channel (ENaC), Na/Cl cotransporter (NCC), and with no-lysine-kinase 1 (WNK1). After dietary K restriction for 2 weeks, compared with control littermates, inducible renal tubular NEDD4-2 knockout ( ) mice exhibited severe hypokalemia and urinary K wasting. Notably, expression of the ROMK K channel did not change in the distal convoluted tubule and decreased slightly in the cortical/medullary collecting duct, whereas BK channel abundance increased in principal cells of the connecting tubule/collecting ducts. However, K restriction also enhanced ENaC expression in mice, and treatment with the ENaC inhibitor, benzamil, reversed excessive K wasting. Moreover, K restriction increased WNK1 and WNK4 expression and enhanced SPAK-mediated NCC phosphorylation in mice, with no change in total NCC. We propose a mechanism in which NEDD4-2 deficiency exacerbates hypokalemia during dietary K restriction primarily through direct upregulation of ENaC, whereas increased BK channel expression has a less significant role. These changes outweigh the compensatory antikaliuretic effects of diminished ROMK expression, increased NCC phosphorylation, and enhanced WNK pathway activity in the distal convoluted tubule. Thus, NEDD4-2 has a crucial role in K conservation through direct and indirect effects on ENaC, distal nephron K channels, and WNK signaling.

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Section: Discussionsupporting

confidence: 72%

Renal Tubular Ubiquitin-Protein Ligase NEDD4-2 Is Required for Renal Adaptation during Long-Term Potassium Depletion

Al‐Qusairi

Basquin

Roy

et al. 2017

JASN

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“…SGK1 is well known for its role in modulating sodium transport in renal epithelial cells of the distal convoluted tubule through upregulation of the epithelial sodium channel (ENaC) and NCC (19 (20,21). Treg cells have been shown to suppress Ang II-induced hypertension and vascular injury (22).…”

Section: Discussionmentioning

confidence: 99%

A salt-sensing kinase in T lymphocytes, SGK1, drives hypertension and hypertensive end-organ damage

et al. 2017

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“…The interaction between Need4‐2 and the PY motif catalyzes ubiquitination of ENaCs, resulting in their internalization and degradation. The gain‐of‐function mutations associated with Liddle syndrome can delete or alter the PY motif, impeding its combination with Need4‐2, and lead to an abnormal turnover of ENaCs and constitutive activation of the ENaC . Volume expansion because of an imbalance in sodium homeostasis in the distal nephron, and possibly other tissues, suppresses renin and aldosterone secretion and leads to severe hypertension.…”

Section: Discussionmentioning

confidence: 99%

Prevalence of Liddle Syndrome Among Young Hypertension Patients of Undetermined Cause in a Chinese Population

Wang

Yang

Jiang

et al. 2015

J of Clinical Hypertension

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Liddle syndrome, an autosomal dominant form of monogenic hypertension, has been regarded as a rare disorder, which leads to many Liddle syndrome patients being misdiagnosed and experiencing severe complications at an early age. Little is known about the prevalence of Liddle syndrome. In this study, the authors investigated the prevalence of Liddle syndrome confirmed by genetic testing among young hypertension patients of undetermined causes in China. A total of 330 hypertensive patients aged 14 to 40 years after exclusion of common secondary causes of hypertension were enrolled and serum potassium concentrations were measured. Patients with hypokalemia underwent genetic testing of the 13th exon of genes encoding β and γ subunits of the epithelial sodium channel (ENaC). Diagnosis was established by identification of mutations that destroy the PY motif of ENaC. Five patients were diagnosed with Liddle syndrome (prevalence, 1.52%), as well as 12 of their relatives. These patients with Liddle syndrome presented with an earlier onset of hypertension, a stronger family history of hypertension, and higher blood pressure than those with essential hypertension. All patients had hypokalemia and suppressed plasma renin activity. The results demonstrated that Liddle syndrome is an important etiology of hypertension in this young population. Screening of Liddle syndrome should focus on young hypertension patients, particularly those with early penetrance, hypokalemia, and low renin levels after exclusion of common secondary causes.

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Ubiquitylation and the pathogenesis of hypertension

Cited by 11 publications

References 20 publications

Renal Tubular Ubiquitin-Protein Ligase NEDD4-2 Is Required for Renal Adaptation during Long-Term Potassium Depletion

Renal Tubular Ubiquitin-Protein Ligase NEDD4-2 Is Required for Renal Adaptation during Long-Term Potassium Depletion

A salt-sensing kinase in T lymphocytes, SGK1, drives hypertension and hypertensive end-organ damage

Prevalence of Liddle Syndrome Among Young Hypertension Patients of Undetermined Cause in a Chinese Population

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