Published Online
on January 3, 2006

A more recent version of this article appeared on February 1, 2006

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Submitted on September 28, 2005
Revised on October 21, 2005

RNA Silencing In Vivo Reveals Role of p22^phox in Rat Angiotensin Slow Pressor Response

Paul Modlinger; Tinatin Chabrashvili; Pritomhinder S. Gill; Margarida Mendonca; David G. Harrison; Kathy K. Griendling; Min Li; Julie Raggio; Anton Wellstein; Yifan Chen; William J. Welch; and Christopher S. Wilcox^*

From the Division of Cardiology (D.G.H., K.K.G.), Emory University, Atlanta, Ga; Angiogenesis Section (P.S.G., A.W., Y.C., W.J.W., C.W.), Lombardi Cancer Center, and Cardiovascular-Kidney Institute and Division of Nephrology and Hypertension (P.M., T.C., P.S.G., M.M., M.L., J.R., Y.C., W.J.W., C.S.W.) Georgetown University, Washington, DC.

^* To whom correspondence should be addressed. E-mail: wilcoxch{at}georgetown.edu.

Abstract--The angiotensin II (Ang II) slow-pressor response entails an increase in mean arterial pressure and reactive oxygen species. We used double-stranded interfering RNAs (siRNAs) in Sprague Dawley rats in vivo to test the hypothesis that an increase in the p22^phox component of NADPH oxidase is required for this response. Reactive oxygen species were assessed from excretion of 8-isoprostane prostaglandin F₂ and blood pressure by telemetry. Two siRNA sequences to p22^phox (sip22^phox) reduced mRNA >85% in cultured vascular smooth muscle cells. Rats received rapid (10 second) IV injections (50 to 100 µg) of 1 of 2 different sip22^phox, control siRNA, or vehicle (TransIt in saline) during 14 day SC infusions of Ang II (200 ng · kg^-1 · min^-1) or sham infusions. In both groups, sip22^phox, relative to control siRNA, led to significant (P<0.001; 50%) reductions in expression of p22^phox mRNA and protein and of NADPH oxidase activity in the kidney cortex. In Ang II-infused rats, sip22^phox decreased protein expression for Nox-1, -2, and -4 but increased p47^phox. Three days after sip22^phox, conscious rats infused with Ang II had a reduced excretion of 8-isoprostane (10±1 versus 19±2 pg · 24 h^-1; P<0.01) and a reduced mean arterial pressure (142±5 versus 168±4 mm Hg; P<0.005). An increase in p22^phox is required for increased renal NADPH oxidase activity, expression of Nox proteins and oxidative stress, and contributes 50% to hypertension during an Ang II slow-pressor response.

Key words: hypertension, arterial • arterioles • oxidative stress • kidney

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