title: Role of epoxyeicosatrienoic acids (EETs) in mediation of dopamine's effects in the kidney.
abstract: We have recently demonstrated that intrarenal dopamine plays an important role in preventing the development of systemic hypertension. Similarly, renal cytochrome P-450 (CYP)-epoxygenase-derived arachidonic acid metabolites, epoxyeicosatrienoic acids (EETs), also are antihypertensive through inhibiting sodium reabsorption and vasodilation. The potential interaction between renal dopamine and epoxygenase systems was investigated. Catechol-O-methyl-transferase (COMT)(-/-) mice with increased intrarenal dopamine levels and proximal tubule deletion of aromatic amino acid decarboxylase (ptAADC(-/-)) mice with renal dopamine deficiency were treated with a low-salt diet or high-salt diet for 2 wk. Wild-type or Cyp2c44(-/-) mice were treated with gludopa, which selectively increased renal dopamine levels. In low salt-treated mice, urinary EET levels were related to renal dopamine levels, being highest in COMT(-/-) mice and lowest in ptAADC(-/-) mice. In high salt-treated mice, total EET and individual EET levels in both the kidney and urine were also highest in COMT(-/-) mice and lowest in ptAADC(-/-) mice. Selective increases in renal dopamine in response to gludopa administration led to marked increases in both total and all individual EET levels in the kidney without any changes in blood levels. qRT-PCR and immunoblotting indicated that gludopa increased renal Cyp2c44 mRNA and protein levels. Gludopa induced marked increases in urine volume and urinary sodium excretion in wild-type mice. In contrast, gludopa did not induce significant increases in urine volume or urinary sodium excretion in Cyp2c44(-/-) mice. These studies demonstrate that renal EET levels are maintained by intrarenal dopamine, and Cyp2c44-derived EETs play an important role in intrarenal dopamine-induced natriuresis and diuresis.
authors.affiliation: Div. of Nephrology, C3121 MCN, Vanderbilt Univ. School of Medicine and Nashville Veterans Affairs Hospital, Nashville, TN 37232. ray.harris@vanderbilt.edu.
authors.forename: Ming-Zhi
authors.initials: MZ
authors.lastname: Zhang
authors.forename: Yinqiu
authors.initials: Y
authors.lastname: Wang
authors.forename: Bing
authors.initials: B
authors.lastname: Yao
authors.forename: Leslie
authors.initials: L
authors.lastname: Gewin
authors.forename: Shouzuo
authors.initials: S
authors.lastname: Wei
authors.forename: Jorge H
authors.initials: JH
authors.lastname: Capdevila
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Harris
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D001142:Aromatic-L-Amino-Acid Decarboxylases / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D002394:Catechol O-Methyltransferase / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D000072467:Cytochrome P450 Family 2; D004039:Diet, Sodium-Restricted; D004295:Dihydroxyphenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology; D004195:Disease Models, Animal; D004231:Diuresis / Q000187:drug effects / Q000502:physiology; D004298:Dopamine / Q000502:physiology*; D015259:Dopamine Agents / Q000378:metabolism*; D006973:Hypertension / Q000378:metabolism* / Q000503:physiopathology; D007668:Kidney / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009318:Natriuresis / Q000187:drug effects / Q000502:physiology; D017673:Sodium Chloride, Dietary / Q000494:pharmacology
chemical_list: D015259:Dopamine Agents; D017673:Sodium Chloride, Dietary; D016718:Arachidonic Acid; C017342:gamma-glutamyl DOPA; D004295:Dihydroxyphenylalanine; D003577:Cytochrome P-450 Enzyme System; C492667:Cyp2c23 protein, mouse; D000090762:Cytochrome P-450 CYP2J2; D000072467:Cytochrome P450 Family 2; D002394:Catechol O-Methyltransferase; D001142:Aromatic-L-Amino-Acid Decarboxylases; D004298:Dopamine
keywords: AADC; COMT; Cyp2c44; EET; dopamine; gludopa; natriuresis