Epoxyeicosatrienoic acids (EETs) regulate epithelial sodium channel activity by extracellular signal-regulated kinase 1/2 (ERK1/2)-mediated phosphorylation
| Autor: | Nataliya Pidkovka, Shaojun Mei, Reena Rao, Yan Gong, Raymond C. Harris, Wen-Hui Wang, Jorge H. Capdevila |
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| Rok vydání: | 2013 |
| Předmět: |
MAPK/ERK pathway
Epoxygenase Epithelial sodium channel Male Cetuximab Antibodies Monoclonal Humanized Kidney Biochemistry Models Biological Mice 8 11 14-Eicosatrienoic Acid Cytochrome P-450 Enzyme System Epidermal growth factor Extracellular Animals Humans Phosphorylation Protein kinase A Cytochrome P450 Family 2 Epithelial Sodium Channels Extracellular Signal-Regulated MAP Kinases Molecular Biology Antihypertensive Agents biology Epidermal Growth Factor Kinase urogenital system Antibodies Monoclonal Molecular Bases of Disease Cell Biology respiratory system Cell biology Gene Expression Regulation Hypertension biology.protein cardiovascular system lipids (amino acids peptides and proteins) hormones hormone substitutes and hormone antagonists |
| Zdroj: | The Journal of biological chemistry. 288(7) |
| ISSN: | 1083-351X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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