Epithelial Sodium Channel

Rossier, Bernard C.; Schild, Laurent

doi:10.1161/hypertensionaha.107.097147

Cited by 67 publications

(27 citation statements)

References 84 publications

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“…Taken together, these studies: (a) show that the Cyp2c44 epoxygenase mediates dietary HS-induced increases in renal EET biosynthesis; (b) demonstrate that a dysfunctional Cyp2c44 gene causes salt-sensitive increases in systemic BP; and (c) identify the Cyp2c44 epoxygenase as a dietary salt-sensitive antihypertensive enzyme and point to roles for its EET metabolites in systemic BP control (21,35). Of interest, the pressure responses of KO mice to dietary salt are similar to those seen in a mouse model of Liddle syndrome with a hyperactive ENaC because of a deletion in the C terminus of ENaC␤ (6).…”

Section: Resultsmentioning

confidence: 87%

“…The kidney epithelial sodium channel (ENaC) plays important roles in the hormonal regulation of sodium reabsorption in the distal nephron and in the fine-tuning of plasma sodium levels (3)(4)(5)(6)(7). ENaC is composed of three subunits: ␣, ␤, and ␤ (ENaC␣, ENaC␤, and ENaC␥, respectively) (8), that mediate inward sodium transport in the apical surface of the collecting duct (CD) principal cells (7)(8)(9).…”

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confidence: 99%

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The Cyp2c44 Epoxygenase Regulates Epithelial Sodium Channel Activity and the Blood Pressure Responses to Increased Dietary Salt

Capdevila

Pidkovka

Mei

et al. 2014

Journal of Biological Chemistry

108

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Background: Epoxyeicosatrienoic acids (EETs) regulate sodium excretion in the distal nephron. Results: Lack of a Cyp2c44 epoxygenase blunts the ERK1/2-mediated inhibition of ENaC and causes salt-sensitive hypertension. Conclusion: Cyp2c44 is the epoxygenase responsible for the synthesis of natriuretic EETs during increased salt intake. Significance: Roles for the human CYP2C8 and CYP2C9 epoxygenases as antihypertensive therapeutic targets are proposed.

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Section: Resultsmentioning

confidence: 87%

mentioning

confidence: 99%

The Cyp2c44 Epoxygenase Regulates Epithelial Sodium Channel Activity and the Blood Pressure Responses to Increased Dietary Salt

Capdevila

Pidkovka

Mei

et al. 2014

Journal of Biological Chemistry

108

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“…2,3 Although sodium transport in ASDN accounts for a small proportion of renal sodium transport (,10%), ENaC activity is the rate-limiting step for this discretionary Na + reabsorption. 4 The Dahl salt-sensitive (SS) rat strain used in this study is a genetic animal model of hypertension and kidney disease that reveals disease traits similar to those observed in humans. This inbred strain exhibits a low-renin, sodium-sensitive form of hypertension that is associated with severe and progressive proteinuria, glomerulosclerosis, and renal interstitial fibrosis.…”

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confidence: 99%

Deficiency of Renal Cortical EGF Increases ENaC Activity and Contributes to Salt-Sensitive Hypertension

Pavlov¹,

Levchenko²,

O’Connor³

et al. 2013

Journal of the American Society of Nephrology

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Various stimuli, including hormones and growth factors, modulate epithelial sodium channels (ENaCs), which fine-tune Na + absorption in the kidney. Members of the EGF family are important for maintaining transepithelial Na + transport, but whether EGF influences ENaC, perhaps mediating salt-sensitive hypertension, is not well understood. Here, the ENaC inhibitor benzamil attenuated the development of hypertension in Dahl salt-sensitive rats. Feeding these salt-sensitive rats a high-salt diet led to lower levels of EGF in the kidney cortex and enhanced the expression and activity of ENaC compared with feeding a lowsalt diet. To directly evaluate the role of EGF in the development of hypertension and its effect on ENaC activity, we infused EGF intravenously while continuously monitoring BP of the salt-sensitive rats. Infusion of EGF decreased ENaC activity, prevented the development of hypertension, and attenuated glomerular and renal tubular damage. Taken together, these findings indicate that cortical EGF levels decrease with a high-salt diet in salt-sensitive rats, promoting ENaC-mediated Na + reabsorption in the collecting duct and the development of hypertension. More than 76 million American adults have high BP 1 and the likelihood of developing hypertension significantly increases with age. Nearly 40% of African Americans aged .20 years exhibit hypertension and nearly 70% of these individuals have a form of hypertension that is highly sensitive to salt intake. A reduced ability to maintain sodium homeostasis and normal levels of arterial pressure is a hallmark of all forms of hypertension. 2 In the kidney, discretionary Na + reabsorption in response to endocrine input to the aldosterone-sensitive distal nephron (ASDN) is a determinant of the pressurenatriuresis relationship, which is of fundamental importance in the long-term control of arterial pressure. 2,3 Although sodium transport in ASDN accounts for a small proportion of renal sodium transport (,10%), ENaC activity is the rate-limiting step for this discretionary Na + reabsorption. 4 The Dahl salt-sensitive (SS) rat strain used in this study is a genetic animal model of hypertension and kidney disease that reveals disease traits similar to those observed in humans. This inbred strain exhibits a low-renin, sodium-sensitive form of hypertension that is associated with severe and progressive proteinuria, glomerulosclerosis, and renal interstitial fibrosis. [5][6][7] The EGF and related hormones are multipotent agents [8][9][10][11] involved in regulation of various renal

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“…Liddle's syndrome is an autosomal dominant disorder causing hyperactivity of the amiloride-sensitive sodium channel (ENaC) in the cortical collecting tubule. 13 Genetic studies…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Preparation for hypertension specialists:

Luft

2014

Journal of the American Society of Hypertension

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Genomics is a discipline in genetics that applies recombinant DNA, DNA sequencing methods, and bioinformatics to sequence, assemble, and analyze the function and structure of genomes, the complete set of DNA within a single cell of an organism. Research into the genetics of hypertension has now expanded to genomics. Two approaches have dominated this field. One relies on large populations in which the phenotype, hypertension versus no hypertension, or hypertension-relevant phenotypes are compared. Genome-wide association (GWAS) analyses of (>1 million) common variants identify relevant loci and possible genes exerting small effects. Detailed studies on APOL1 and SH2B3 are opening entire new fields of research. Family-based Mendelian studies have identified rare variants that exert very large effects on blood pressure. Mechanistically, these studies have been a bonanza of new information. The approaches are complementary. Genome-wide association studiesEssential (primary) hypertension results from many environmental and genetic factors.Candidate-gene, genome-wide linkage, and genome-wide association studies (GWAS) relying on single-nucleotide polymorphisms (SNPs) have all given insights into genes relevant for essential hypertension. Candidate gene studies have implicated aberrations in aldosterone signaling, catecholamine pathways, ion channel regulation, and inflammatory pathways. For GWAS, massive sample sizes have been used (>80,000 individuals) to find gene loci that exert only modest effects. Memorizing these genes and their variants seems counterproductive since thus far they collectively explain only about 2.5% of blood pressure variation. Nevertheless, ranking all the currently known findings could theoretically produce a genetic risk score indicating a 25% increase in the odds of developing essential hypertension.High-throughput massive parallel sequencing and the plummeting costs (currently about

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Epithelial Sodium Channel

Cited by 67 publications

References 84 publications

The Cyp2c44 Epoxygenase Regulates Epithelial Sodium Channel Activity and the Blood Pressure Responses to Increased Dietary Salt

The Cyp2c44 Epoxygenase Regulates Epithelial Sodium Channel Activity and the Blood Pressure Responses to Increased Dietary Salt

Deficiency of Renal Cortical EGF Increases ENaC Activity and Contributes to Salt-Sensitive Hypertension

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