title: COX-2 is involved in vascular oxidative stress and endothelial dysfunction of renal interlobar arteries from obese Zucker rats.
abstract: Obesity is related to vascular dysfunction through inflammation and oxidative stress and it has been identified as a risk factor for chronic renal disease. In the present study, we assessed the specific relationships among reactive oxygen species (ROS), cyclooxygenase 2 (COX-2), and endothelial dysfunction in renal interlobar arteries from a genetic model of obesity/insulin resistance, the obese Zucker rats (OZR). Relaxations to acetylcholine (ACh) were significantly reduced in renal arteries from OZR compared to their counterpart, the lean Zucker rat (LZR), suggesting endothelial dysfunction. Blockade of COX with indomethacin and with the selective blocker of COX-2 restored the relaxations to ACh in obese rats. Selective blockade of the TXA2/PGH2 (TP) receptor enhanced ACh relaxations only in OZR, while inhibition of the prostacyclin (PGI2) receptor (IP) enhanced basal tone and inhibited ACh vasodilator responses only in LZR. Basal production of superoxide was increased in arteries of OZR and involved NADPH and xanthine oxidase activation and NOS uncoupling. Under conditions of NOS blockade, ACh induced vasoconstriction and increased ROS generation that were augmented in arteries from OZR and blunted by COX-2 inhibition and by the ROS scavenger tempol. Hydrogen peroxide (H2O2) evoked both endothelium- and vascular smooth muscle (VSM)-dependent contractions, as well as ROS generation that was reduced by COX-2 inhibition. In addition, COX-2 expression was enhanced in both VSM and endothelium of renal arteries from OZR. These results suggest that increased COX-2-dependent vasoconstriction contributes to renal endothelial dysfunction through enhanced (ROS) generation in obesity. COX-2 activity is in turn upregulated by ROS.
authors.affiliation: Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense, Madrid 28040, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Muñoz
authors.affiliation: Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense, Madrid 28040, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Sánchez
authors.affiliation: Departamento de Anatomía and Anatomía Patológica Comparadas, Facultad de Veterinaria, Universidad Complutense, Madrid 28040, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Pilar Martínez
authors.affiliation: Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense, Madrid 28040, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Benedito
authors.affiliation: Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense, Madrid 28040, Spain.
authors.forename: Maria-Elvira
authors.initials: ME
authors.lastname: López-Oliva
authors.affiliation: Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense, Madrid 28040, Spain.
authors.forename: Albino
authors.initials: A
authors.lastname: García-Sacristán
authors.affiliation: Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense, Madrid 28040, Spain.
authors.forename: Medardo
authors.initials: M
authors.lastname: Hernández
authors.affiliation: Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense, Madrid 28040, Spain. Electronic address: dprieto@ucm.es.
authors.forename: Dolores
authors.initials: D
authors.lastname: Prieto
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000502:physiology*; D004730:Endothelium, Vascular / Q000201:enzymology / Q000503:physiopathology; D007668:Kidney / Q000098:blood supply; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009765:Obesity / Q000201:enzymology* / Q000503:physiopathology; D018384:Oxidative Stress; D011924:Rats, Zucker; D017382:Reactive Oxygen Species / Q000378:metabolism; D012077:Renal Artery / Q000201:enzymology / Q000503:physiopathology; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology; D014664:Vasodilation; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D008565:Membrane Proteins; D020030:Nitric Oxide Donors; D017382:Reactive Oxygen Species; D014665:Vasodilator Agents; D026423:S-Nitroso-N-Acetylpenicillamine; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496513:Ptgs1 protein, rat; C489691:Ptgs2 protein, rat; D000109:Acetylcholine
keywords: COX-2; Endothelial dysfunction; Obesity; Oxidative stress; Renal arteries