CYP epoxygenase-derived H 2 O 2 is involved in the endothelium-derived hyperpolarization (EDH) and relaxation of intrarenal arteries

• Published in: Free radical biology & medicine 2017-05, Vol.106, p.168-183
• Main Authors: Muñoz, Mercedes, López-Oliva, Maria Elvira, Pinilla, Estéfano, Martínez, María Pilar, Sánchez, Ana, Rodríguez, Claudia, García-Sacristán, Albino, Hernández, Medardo, Rivera, Luis, Prieto, Dolores
• Format: Article
• Language: English
• Subjects: Acetophenones - administration & dosage; Acetylcholine - metabolism; Animals; Arteries - drug effects; Arteries - metabolism; Aryl Hydrocarbon Hydroxylases - metabolism; Biological Factors - metabolism; Calcium - metabolism; Cytochrome P-450 Enzyme System - metabolism; Cytochrome P450 Family 2 - metabolism; Endothelium - drug effects; Endothelium - metabolism; Humans; Hydrogen Peroxide - metabolism; Kidney - metabolism; Kidney - pathology; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - metabolism; Muscle, Smooth, Vascular - pathology; NADPH Oxidases - metabolism; Nitric Oxide Synthase - genetics; Nitric Oxide Synthase Type III; Prostaglandin-Endoperoxide Synthases - genetics; Prostaglandin-Endoperoxide Synthases - metabolism; Rats; Reactive Oxygen Species - metabolism; Relaxation; Steroid 16-alpha-Hydroxylase - metabolism; Sulfaphenazole - administration & dosage; Superoxides - metabolism
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2017.02.031

Reactive oxygen species (ROS) like hydrogen peroxide (H O ) 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 H O is 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 H O release that were reduced by catalase and by the glutathione peroxidase (GPx) mimetic ebselen in rat renal interlobar arteries, suggesting the involvement of H O in 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 (O ) and H O production that were reduced by sulfaphenazole and apocynin. Expression of the antioxidant enzyme CuZnSOD and of the H O reducing enzymes catalase and GPx-1 was found in both intrarenal arteries and renal cortex. On the other hand, exogenous H O relaxed renal arteries by decreasing vascular smooth muscle (VSM) intracellular calcium concentration [Ca ] and markedly enhanced endothelial K currents 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 H O is involved in the EDH-type relaxant responses of renal arteries and that CYP 2C epoxygenases are physiologically relevant endothelial sources of vasodilator H O in the kidney.