ArticleThe Journal of biological chemistry2013
Epoxyeicosatrienoic acids (EETs) regulate epithelial sodium channel activity by extracellular signal-regulated kinase 1/2 (ERK1/2)-mediated phosphorylation.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 39 citations in OpenAlex.
- GLIS3, a novel regulator of eicosanoid gene expression and metabolism in normal kidney and polycystic kidney disease.Biochemical pharmacology · 2026Article
- Regulation of P450-derived epoxy fatty acids in cardiovascular diseases.Redox biochemistry and chemistry · 2025Article
- CD148 agonistic antibody alleviates renal injury induced by chronic angiotensin II infusion in mice.BMC nephrology · 2025Article
- Epoxyeicosatrienoic acids (EETs): A novel class of second messengers of hormonal functional responses.Prostaglandins & other lipid mediators · 2025Review
- Article
- Eicosanoid-Regulated Myeloid ENaC and Isolevuglandin Formation in Human Salt-Sensitive Hypertension.Hypertension (Dallas, Tex. : 1979) · 2024Article
- The involvement of soluble epoxide hydrolase in the development of cardiovascular diseases through epoxyeicosatrienoic acids.Frontiers in pharmacology · 2024Review
- Gene Polymorphism and Recurrent Atrial Fibrillation after Catheter Ablation: A Comprehensive Review.Reviews in cardiovascular medicine · 2023Review
- Urinary proteomics reveals key markers of salt sensitivity in hypertensive patients during saline infusion.Journal of nephrology · 2021Article
- The Vanderbilt O'Brien Kidney Center.American journal of physiology. Renal physiology · 2021Review
- Extrahepatic cytochrome P450 epoxygenases: pathophysiology and clinical significance in human gastrointestinal cancers.Oncotarget · 2021Review
- Epoxyeicosatrienoic acid metabolites inhibit Kir4.1/Kir5.1 in the distal convoluted tubule.American journal of physiology. Renal physiology · 2020Article
- Prospective for cytochrome P450 epoxygenase cardiovascular and renal therapeutics.Pharmacology & therapeutics · 2018Review
- A novel dual PPAR-γ agonist/sEH inhibitor treats diabetic complications in a rat model of type 2 diabetes.Diabetologia · 2018Article
- Orally Active Epoxyeicosatrienoic Acid Analogs.Journal of cardiovascular pharmacology · 2017Review
- Structural determinants of 5',6'-epoxyeicosatrienoic acid binding to and activation of TRPV4 channel.Scientific reports · 2017Article
- Midkine Regulates BP through Cytochrome P450-Derived Eicosanoids.Journal of the American Society of Nephrology : JASN · 2015Article
- Arachidonic acid monooxygenase: Genetic and biochemical approaches to physiological/pathophysiological relevance.Prostaglandins & other lipid mediators · 2015Review
- Cholesterol affects flow-stimulated cyclooxygenase-2 expression and prostanoid secretion in the cortical collecting duct.American journal of physiology. Renal physiology · 2015Article
- Cytochrome P450 epoxygenase pathway of polyunsaturated fatty acid metabolism.Biochimica et biophysica acta · 2015Review
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
Abstract
The epithelial sodium channel (ENaC) participates in the regulation of plasma sodium and volume, and gain of function mutations in the human channel cause salt-sensitive hypertension. Roles for the arachidonic acid epoxygenase metabolites, the epoxyeicosatrienoic acids (EETs), in ENaC activity have been identified; however, their mechanisms of action remain unknown. In polarized M1 cells, 14,15-EET inhibited amiloride-sensitive apical to basolateral sodium transport as effectively as epidermal growth factor (EGF). The EET effects were associated with increased threonine phosphorylation of the ENaC β and γ subunits and abolished by inhibitors of (a) mitogen-activated protein kinase/extracellular signal-regulated kinase kinase/extracellular signal regulated kinases 1 and 2 (MEK/ERK1/2) and (b) EGF receptor signaling. CYP2C44 epoxygenase knockdown blunted the sodium transport effects of EGF, and its 14,15-EET metabolite rescued the knockdown phenotype. The relevance of these findings is indicated by (a) the hypertension that results in mice administered cetuximab, an inhibitor of EGF receptor binding, and (b) immunological data showing an association between the pressure effects of cetuximab and reductions in ENaCγ phosphorylation. These studies (a) identify an ERK1/2-dependent mechanism for ENaC inhibition by 14,15-EET, (b) point to ENaC as a proximal target for EET-activated ERK1/2 mitogenic kinases, (c) characterize a mechanistic commonality between EGF and epoxygenase metabolites as ENaC inhibitors, and (d) suggest a CYP2C epoxygenase-mediated pathway for the regulation of distal sodium transport.
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Registered trials
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