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(Hypertension. 2009;54:1106.)
© 2009 American Heart Association, Inc.

Original Articles

Genetic Silencing of Nox2 and Nox4 Reveals Differential Roles of These NADPH Oxidase Homologues in the Vasopressor and Dipsogenic Effects of Brain Angiotensin II

Jeffrey R. Peterson; Melissa A. Burmeister; Xin Tian; Yi Zhou; Mallikarjuna R. Guruju; John A. Stupinski; Ram V. Sharma; Robin L. Davisson

From the Department of Cell and Developmental Biology (J.R.P., M.R.G., R.V.S., R.L.D.), Weill Cornell Medical College, New York, N.Y.; Biomedical Sciences (M.A.B., Y.Z., J.A.S., R.V.S., R.L.D.), College of Veterinary Medicine, Cornell University, Ithaca, N.Y.; Department of Anatomy and Cell Biology (X.T.), University of Iowa, Iowa City, Iowa.

Correspondence to Robin L. Davisson, Biomedical Sciences, College of Veterinary Medicine and Cell and Developmental Biology, Weill Cornell Medical College, T9-014 Veterinary Research Tower, Cornell University, Ithaca, NY 14853-6401. E-mail robin.davisson{at}cornell.edu

The renin-angiotensin system exerts a tremendous influence over fluid balance and arterial pressure. Angiotensin II (Ang-II), the effector peptide of the renin-angiotensin system, acts in the central nervous system to regulate neurohumoral outflow and thirst. Dysregulation of Ang-II signaling in the central nervous system is implicated in cardiovascular diseases; however, the mechanisms remain poorly understood. Recently we established that NADPH oxidase (Nox)–derived superoxide acting in the forebrain subfornical organ is critical in the physiological responses to central Ang-II. In addition, we have found that Nox2 and Nox4 are the most abundantly expressed Nox homologues within Ang-II–sensitive sites in the forebrain. To dissect out the functional importance and unique roles of these Nox enzymes in the pressor and dipsogenic effects of central Ang-II, we developed adenoviral vectors expressing small interfering RNA to selectively silence Nox2 or Nox4 expression in the subfornical organ. Our results demonstrate that both Nox2 and Nox4 are required for the full vasopressor effects of brain Ang-II but that only Nox2 is coupled to the Ang-II–induced water intake response. These studies establish the importance of both Nox2- and Nox4-containing NADPH oxidases in the actions of Ang-II in the central nervous system and are the first to reveal differential involvement of these Nox enzymes in the various physiological effects of central Ang-II.

Key Words: hypertension • blood pressure • water intake • subfornical organ • adenovirus • siRNA