title: Cyp2c44 epoxygenase is essential for preventing the renal sodium absorption during increasing dietary potassium intake.
abstract: The aim of this study is to test whether the Cyp2c44 epoxygenase-dependent metabolism of arachidonic acid prevents the hypertensive effect of a high K (HK) intake by inhibiting the epithelial sodium channel (ENaC) activity. A HK intake elevated Cyp2c44 mRNA expression and 11,12-epoxyeicosatrienoic acid levels in the cortical collecting duct in Cyp2c44(+/+) mice (wild-type [wt]). However, an HK intake failed to increase 11,12-epoxyeicosatrienoic acid formation in the cortical collecting ducts of Cyp2c44(-/-) mice. Moreover, increasing K intake enhanced arachidonic acid-induced inhibition of ENaC in the wt but not in Cyp2c44(-/-) mice. In contrast, 11,12-epoxyeicosatrienoic acid, a Cyp2c44 metabolite, inhibited ENaC in the wt and Cyp2c44(-/-) mice. The notion that Cyp2c44 is the epoxygenase responsible for mediating the inhibitory effects of arachidonic acid on ENaC is further suggested by the observation that inhibiting Cyp-epoxygenase increased the whole-cell Na currents in principal cells of wt but not in Cyp2c44(-/-) mice. Feeding mice with an HK diet raised the systemic blood pressures of Cyp2c44(-/-) mice but was without an effect on wt mice. Moreover, application of amiloride abolished the HK-induced hypertension in Cyp2c44(-/-) mice. The HK-induced hypertension of Cyp2c44(-/-) mice was accompanied by decreasing 24-hour urinary Na excretion and increasing the plasma Na concentration, and the effects were absent in wt mice. In contrast, disruption of the Cyp2c44 gene did not alter K excretion. We conclude that Cyp2c44 epoxygenase mediates the inhibitory effect of arachidonic acid on ENaC and that Cyp2c44 functions as an HK-inducible antihypertensive enzyme responsible for inhibiting ENaC activity and Na absorption in the aldosterone-sensitive distal nephron.
authors.affiliation: Department of Pharmacology, New York Medical College, 15 Dana Rd, Valhalla, NY 10595, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Sun
authors.forename: Joseph
authors.initials: J
authors.lastname: Antoun
authors.forename: Dao-Hong
authors.initials: DH
authors.lastname: Lin
authors.forename: Peng
authors.initials: P
authors.lastname: Yue
authors.forename: Katherine H
authors.initials: KH
authors.lastname: Gotlinger
authors.forename: Jorge
authors.initials: J
authors.lastname: Capdevila
authors.forename: Wen-Hui
authors.initials: WH
authors.lastname: Wang
mesh_terms: D000042:Absorption / Q000502:physiology; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D003577:Cytochrome P-450 Enzyme System / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D053503:Epithelial Sodium Channels / Q000378:metabolism; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000494:pharmacology; D017419:Potassium, Dietary / Q000494:pharmacology*; D012964:Sodium / Q000378:metabolism*
chemical_list: D053503:Epithelial Sodium Channels; D017419:Potassium, Dietary; D016718:Arachidonic Acid; D003577:Cytochrome P-450 Enzyme System; D012964:Sodium; C492667:Cyp2c23 protein, mouse; D000072467:Cytochrome P450 Family 2; D011188:Potassium