title: Cyp2c44 epoxygenase in the collecting duct is essential for the high K+ intake-induced antihypertensive effect.
abstract: Cytochrome P-450, family 2, subfamily c, polypeptide 44 (Cyp2c44) epoxygenase metabolizes arachidonic acid (AA) to epoxyeicosatrienoic acids (EETs) in kidney and vascular tissues. In the present study, we used real-time quantitative PCR techniques to examine the effect of high salt or high K(+) (HK) intake on the expression of Cyp2c44, a major Cyp2c epoxygenase in the mouse kidney. We detected Cyp2c44 in the proximal convoluted tubule, thick ascending limb, distal convoluted tubule (DCT)/connecting tubule (CNT), and collecting duct (CD). A high-salt diet increased the expression of Cyp2c44 in the thick ascending limb and DCT/CNT but not in the proximal convoluted tubule and CD. In contrast, an increase in dietary K(+) intake augmented Cyp2c44 expression only in the DCT/CNT and CD. Neither high salt nor HK intake had a significant effect on the blood pressure (BP) of wild-type mice. However, HK but not high salt intake increased BP in CD-specific, Cyp2c44 conditional knockout (KO) mice. Amiloride, an epithelial Na(+) channel (ENaC) inhibitor, normalized the BP of KO mice fed HK diets, suggesting that lack of Cyp2c44 in the CD enhances ENaC activity and increases Na(+) absorption in KO mice fed HK diets. This notion was supported by metabolic cage experiments demonstrating that renal Na(+) excretion was compromised in KO mice fed HK diets. Also, patch-clamp experiments demonstrated that 11,12-EET, a major Cyp2c44 product, but not AA inhibited ENaC activity in the cortical CD of KO mice. We conclude that Cyp2c44 in the CD is required for preventing the excessive Na(+) absorption induced by HK intake by inhibition of ENaC and facilitating renal Na(+) excretion.
authors: Department of Pharmacology, New York Medical College, Valhalla, New York; Wenhui_wang@nymc.edu.
authors: Wen-Hui
authors: WH
authors: Wang
authors: Department of Pharmacology, New York Medical College, Valhalla, New York;
authors: Chengbiao
authors: C
authors: Zhang
authors: Department of Pharmacology, New York Medical College, Valhalla, New York;
authors: Dao-Hong
authors: DH
authors: Lin
authors: Department of Pharmacology, New York Medical College, Valhalla, New York;
authors: Lijun
authors: L
authors: Wang
authors: Division of Intramural Research, National Institute of Environmental Health Science, Research Triangle Park, North Carolina; and.
authors: Joan P
authors: JP
authors: Graves
authors: Division of Intramural Research, National Institute of Environmental Health Science, Research Triangle Park, North Carolina; and.
authors: Darryl C
authors: DC
authors: Zeldin
authors: Department of Medicine, Vanderbilt University, Nashville, Tennessee.
authors: Jorge H
authors: JH
authors: Capdevila
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000502:physiology*; D000072467:Cytochrome P450 Family 2; D053503:Epithelial Sodium Channels / Q000187:drug effects / Q000502:physiology*; D007685:Kidney Tubules, Collecting / Q000378:metabolism; D007686:Kidney Tubules, Distal / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000008:administration & dosage*; D012964:Sodium / Q000652:urine; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage / Q000378:metabolism
chemical_list: D053503:Epithelial Sodium Channels; D017673:Sodium Chloride, Dietary; D016718:Arachidonic Acid; C046783:11,12-epoxy-5,8,14-eicosatrienoic acid; D000584:Amiloride; D003577:Cytochrome P-450 Enzyme System; D012964:Sodium; C492667:Cyp2c23 protein, mouse; D000072467:Cytochrome P450 Family 2; D015126:8,11,14-Eicosatrienoic Acid; D011188:Potassium
keywords: cytochrome P-450, family 2, subfamily c, polypeptide 44; epithelial Na+ channel; epoxyeicosatrienoic acid; hypertension; renal sodium excretion