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(Hypertension. 2008;51:500.)
© 2008 American Heart Association, Inc.

Original Articles Part 2

Renal Redox-Sensitive Signaling, but Not Blood Pressure, Is Attenuated by Nox1 Knockout in Angiotensin II–Dependent Chronic Hypertension

Alvaro Yogi; Chantal Mercure; Joshuah Touyz; Glaucia E. Callera; Augusto C.I. Montezano; Anna B. Aranha; Rita C. Tostes; Timothy Reudelhuber; Rhian M. Touyz

From the Kidney Research Center (A.Y., G.E.C., A.C.I.M., A.B.A., R.M.T.), Ontario Health Research Institute, University of Ottawa, Ottawa, Ontario, Canada; the Clinical Research Institute of Montreal (C.M., J.T., T.R.), Montreal, Quebec, Canada; and the Institute of Biomedical Sciences (A.Y., R.C.T.), University of Sao Paulo, Sao Paulo, Brazil.

Correspondence to Rhian M. Touyz, Kidney Research Centre, University of Ottawa/Ottawa Health Research Institute, 451 Smyth Rd, Ottawa, Ontario, KIH 8M5 Canada. E-mail rtouyz{at}uottawa.ca

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.

Key Words: Nox1 • hypertension • angiotensin II • redox signaling

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