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J. Biol. Chem., Vol. 281, Issue 46, 35137-35146, November 17, 2006

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Angiotensin II-induced NADPH Oxidase Activation Impairs Insulin Signaling in Skeletal Muscle Cells^*

Yongzhong Wei, James R. Sowers^¶1, Ravi Nistala, Heping Gong, Grace M.-E. Uptergrove, Suzanne E. Clark, E. Matthew Morris, Nicholas Szary, Camila Manrique, and Craig S. Stump^¶2

From the Department of Internal Medicine and the ^¶Department of Pharmacology and Physiology, University of Missouri-Columbia 65212 and the Harry S. Truman Memorial Veterans Medical Center, Columbia, Missouri 65201

The renin-angiotensin system (RAS) and reactive oxygen species (ROS) have been implicated in the development of insulin resistance and its related complications. There is also evidence that angiotensin II (Ang II)-induced generation of ROS contributes to the development of insulin resistance in skeletal muscle, although the precise mechanisms remain unknown. In the present study, we found that Ang II markedly enhanced NADPH oxidase activity and consequent ROS generation in L6 myotubes. These effects were blocked by the angiotensin II type 1 receptor blocker losartan, and by the NADPH oxidase inhibitor apocynin. Ang II also promoted the translocation of NADPH oxidase cytosolic subunits p47^phox and p67^phox to the plasma membrane within 15 min. Furthermore, Ang II abolished insulin-induced tyrosine phosphorylation of insulin receptor substrate 1 (IRS1), activation of protein kinase B (Akt), and glucose transporter-4 (GLUT4) translocation to the plasma membrane, which was reversed by pretreating myotubes with losartan or apocynin. Finally, small interfering RNA (siRNA)-specific gene silencing targeted specifically against p47^phox (p47siRNA), in both L6 and primary myotubes, reduced the cognate protein expression, decreased NADPH oxidase activity, restored Ang II-impaired IRS1 and Akt activation as well as GLUT4 translocation by insulin. These results suggest a pivotal role for NADPH oxidase activation and ROS generation in Ang II-induced inhibition of insulin signaling in skeletal muscle cells.

Received for publication, February 10, 2006 , and in revised form, September 12, 2006.

^* This work was supported in part by VA VISN 15 and ARCD awards (to C. S. S.) and National Institutes of Health 5R01 HL073101-02 and VA Merit 0018 (to J. R. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Present address: Dept. of Medicine, University of Arizona, Diabetes Research Center, 1656 E. Mabel St., P.O. 245218, Tucson, AZ 85724-5218. E-mail: sowers{at}email.arizona.edu.

² To whom correspondence should be addressed: Dept. of Medicine, University of Arizona, Diabetes Research Center, 1656 E. Mabel St., P.O. 245218, Tucson, AZ 85724-5218. E-mail: stumpc{at}email.arizona.edu.

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