title: CYP epoxygenase-derived H2O2is involved in the endothelium-derived hyperpolarization (EDH) and relaxation of intrarenal arteries.
abstract: Reactive oxygen species (ROS) like hydrogen peroxide (H2O2) are involved in the in endothelium-derived hyperpolarization (EDH)-type relaxant responses of coronary and mesenteric arterioles. The role of ROS in kidney vascular function has mainly been investigated in the context of harmful ROS generation associated to kidney disease. The present study was sought to investigate whether H2O2is involved in the endothelium-dependent relaxations of intrarenal arteries as well the possible endothelial sources of ROS generation involved in these responses. Under conditions of cyclooxygenase (COX) and nitric oxide (NO) synthase inhibition, acetylcholine (ACh) induced relaxations and stimulated H2O2release that were reduced by catalase and by the glutathione peroxidase (GPx) mimetic ebselen in rat renal interlobar arteries, suggesting the involvement of H2O2in the endothelium-dependent responses. ACh relaxations were also blunted by the CYP2C inhibitor sulfaphenazole and by the NADPH oxidase inhibitor apocynin. Acetylcholine stimulated both superoxide (O2•-) and H2O2production that were reduced by sulfaphenazole and apocynin. Expression of the antioxidant enzyme CuZnSOD and of the H2O2reducing enzymes catalase and GPx-1 was found in both intrarenal arteries and renal cortex. On the other hand, exogenous H2O2relaxed renal arteries by decreasing vascular smooth muscle (VSM) intracellular calcium concentration [Ca2+]iand markedly enhanced endothelial KCacurrents in freshly isolated renal endothelial cells. CYP2C11 and CYP2C23 epoxygenases were highly expressed in interlobar renal arteries and renal cortex, respectively, and were co-localized with eNOS in renal endothelial cells. These results demonstrate that H2O2is involved in the EDH-type relaxant responses of renal arteries and that CYP 2C epoxygenases are physiologically relevant endothelial sources of vasodilator H2O2in the kidney.
authors.affiliation: Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040-Madrid, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Muñoz
authors.affiliation: Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040-Madrid, Spain.
authors.forename: Maria Elvira
authors.initials: ME
authors.lastname: López-Oliva
authors.affiliation: Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040-Madrid, Spain.
authors.forename: Estéfano
authors.initials: E
authors.lastname: Pinilla
authors.affiliation: Departamento de Anatomía and Anatomía Patológica Comparadas, Facultad de Veterinaria, Universidad Complutense de Madrid, 28040-Madrid, Spain.
authors.forename: María Pilar
authors.initials: MP
authors.lastname: Martínez
authors.affiliation: Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040-Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Sánchez
authors.affiliation: Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040-Madrid, Spain.
authors.forename: Claudia
authors.initials: C
authors.lastname: Rodríguez
authors.affiliation: Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040-Madrid, Spain.
authors.forename: Albino
authors.initials: A
authors.lastname: García-Sacristán
authors.affiliation: Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040-Madrid, Spain.
authors.forename: Medardo
authors.initials: M
authors.lastname: Hernández
authors.affiliation: Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040-Madrid, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Rivera
authors.affiliation: Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040-Madrid, Spain. Electronic address: dprieto@ucm.es.
authors.forename: Dolores
authors.initials: D
authors.lastname: Prieto
mesh_terms: D000098:Acetophenones / Q000008:administration & dosage; D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000378:metabolism; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D001685:Biological Factors / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2 / Q000378:metabolism*; D004727:Endothelium / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D019255:NADPH Oxidases / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics; D052250:Nitric Oxide Synthase Type III; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D012063:Relaxation; D039181:Steroid 16-alpha-Hydroxylase / Q000378:metabolism*; D013426:Sulfaphenazole / Q000008:administration & dosage; D013481:Superoxides / Q000378:metabolism
chemical_list: D000098:Acetophenones; D001685:Biological Factors; C000717351:Cyp2c23 protein, rat; D017382:Reactive Oxygen Species; C067410:endothelium-dependent hyperpolarization factor; D013426:Sulfaphenazole; D013481:Superoxides; D003577:Cytochrome P-450 Enzyme System; C056165:acetovanillone; D006861:Hydrogen Peroxide; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; D000090762:Cytochrome P-450 CYP2J2; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; D011451:Prostaglandin-Endoperoxide Synthases; D019255:NADPH Oxidases; D000109:Acetylcholine; D002118:Calcium
keywords: Cytochrome P450 (CYP); Endothelium; Endothelium-derived-hyperpolarization (EDH); H(2)O(2); Renal arteries