title: Renal redox-sensitive signaling, but not blood pressure, is attenuated by Nox1 knockout in angiotensin II-dependent chronic hypertension.
abstract: We demonstrated previously that, in mice with chronic angiotensin II-dependent hypertension, gp91phox-containing NADPH oxidase is not involved in the development of high blood pressure, despite being important in redox signaling. Here we sought to determine whether a gp91phox homologue, Nox1, may be important in blood pressure elevation and activation of redox-sensitive pathways in a model in which the renin-angiotensin system is chronically upregulated. Nox1-deficient mice and transgenic mice expressing human renin (TTRhRen) were crossed, and 4 genotypes were generated: control, TTRhRen, Nox1-deficient, and TTRhRen Nox1-deficient. Blood pressure and oxidative stress (systemic and renal) were increased in TTRhRen mice (P<0.05). This was associated with increased NADPH oxidase activation. Nox1 deficiency had no effect on the development of hypertension in TTRhRen mice. Phosphorylation of c-Src, mitogen-activated protein kinases, and focal adhesion kinase was significantly increased 2- to 3-fold in kidneys from TTRhRen mice. Activation of c-Src, p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, and focal adhesion kinase but not of extracellular signal regulated kinase 1/2 or extracellular signal regulated kinase 5, was reduced in TTRhRen/Nox1-deficient mice (P<0.05). Expression of procollagen III was increased in TTRhRen and TTRhRen/Nox1-deficient mice versus control mice, whereas vascular cell adhesion molecule-1 was only increased in TTRhRen mice. Our findings demonstrate that, in Nox1-deficient TTRhRen mice, blood pressure is elevated despite reduced NADPH oxidase activation, decreased oxidative stress, and attenuated redox signaling. Our results suggest that Nox1-containing NADPH oxidase plays a key role in the modulation of systemic and renal oxidative stress and redox-dependent signaling but not in the elevation of blood pressure in a model of chronic angiotensin II-dependent hypertension.
authors.affiliation: Kidney Research Centre, Ontario Health Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Yogi
authors.forename: Chantal
authors.initials: C
authors.lastname: Mercure
authors.forename: Joshuah
authors.initials: J
authors.lastname: Touyz
authors.forename: Glaucia E
authors.initials: GE
authors.lastname: Callera
authors.forename: Augusto C I
authors.initials: AC
authors.lastname: Montezano
authors.forename: Anna B
authors.initials: AB
authors.lastname: Aranha
authors.forename: Rita C
authors.initials: RC
authors.lastname: Tostes
authors.forename: Timothy
authors.initials: T
authors.lastname: Reudelhuber
authors.forename: Rhian M
authors.initials: RM
authors.lastname: Touyz
mesh_terms: D000804:Angiotensin II; D000818:Animals; D001794:Blood Pressure; D000081247:CSK Tyrosine-Protein Kinase; D002908:Chronic Disease; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D007668:Kidney / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000172:deficiency* / Q000378:metabolism; D000074624:NADPH Oxidase 1; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010766:Phosphorylation; D011347:Procollagen / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012083:Renin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013599:Systole; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D019061:src-Family Kinases
chemical_list: D011347:Procollagen; D020033:Protein Isoforms; D019010:Vascular Cell Adhesion Molecule-1; D000804:Angiotensin II; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; C000614711:NOX1 protein, mouse; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019061:src-Family Kinases; C000631346:CSK protein, human; D020928:Mitogen-Activated Protein Kinases; D012083:Renin