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Am J Physiol Endocrinol Metab (December 11, 2007). doi:10.1152/ajpendo.00456.2007
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Submitted on July 16, 2007
Accepted on December 7, 2007

Angiotensin II-induced skeletal muscle insulin resistance is mediated by NF-{kappa}B activation via NADPH oxidase

Yongzhong Wei1, James R Sowers2, Suzanne E. Clark2, Wenhan Li2, Carlos M Ferrario3, and Craig S Stump4*

1 Harry S. Truman Memorial VA Hospital, Columbia, Missouri, United States
2 Internal Medicine, University of Missouri-Columbia, Columbia, Missouri, United States; Harry S. Truman Memorial VA Hospital, Columbia, Missouri, United States
3 Hypertension Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States
4 Medicine, University of Arizona, Tucson, Arizona, United States; Southern Arizona VA Health Care System, Tucson, Arizona, United States

* To whom correspondence should be addressed. E-mail: stumpc{at}email.arizona.edu.

Reduced insulin sensitivity is a key factor in the pathogenesis of type 2 diabetes and hypertension. Skeletal muscle insulin resistance is particularly important as the major site for insulin-mediated glucose disposal. Angiotensin II (Ang II) is integral in regulating blood pressure and plays a role in the pathogenesis of hypertension. In addition, we have documented that Ang II-induced skeletal muscle insulin resistance is associated with reactive oxygen species (ROS) generation. However, the linkage between ROS and insulin resistance in skeletal muscle remains unclear. To explore potential mechanisms, we employed the transgenic TG(mRen2)27 (Ren2) hypertensive rat that harbors the mouse renin transgene exhibits elevated tissue Ang II levels, and skeletal muscle cell culture. Compared with Sprague Dawley (SD) normtensive control rats, Ren2 skeletal muscle exhibited significantly increased oxidative stress, NF-{kappa}B activation and TNF-{alpha} expression, which were attenuated by in vivo treatment with either an angiotensin type 1 receptor (AT1R) blocker (valsartan) or superoxide dismutase (SOD) /catalase mimetic (tempol). Moreover, Ang II treatment of L6 myotubes induced NF-{kappa}B activation and TNF-{alpha} production, and decreased insulin-stimulated Akt activation and GLUT4 glucose transporter translocation to plasma membranes. These effects were markedly diminished when myotubes were pre-treated with valsartan, antioxidant N-acetylcysteine (NAC), NADPH oxidase inhibiting peptide (gp91ds-tat), or NF-{kappa}B inhibitor (MG132). Similarly, NF-{kappa}B p65 siRNA reduced NF-{kappa}B p65 subunit expression and nuclear translocation, TNF-{alpha} production, while improving insulin-stimulated Akt Ser473 phosphorylation and GLUT4 translocation. These findings suggest that NF-{kappa}B plays an important role in Ang II/ROS-induced skeletal muscle insulin resistance.




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