Angiotensin II-induced skeletal muscle insulin resistance mediated by NF-κB activation via NADPH oxidase

Yongzhong Wei, James R. Sowers, Suzanne E. Clark, Wenhan Li, Carlos M. Ferrario, Craig S. Stump

Research output: Contribution to journalArticlepeer-review

158 Scopus citations

Abstract

Reduced insulin sensitivity is a key factor in the pathogenesis of type 2 diabetes and hypertension. Skeletal muscle insulin resistance is particularly important for its major role in 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 generation of reactive oxygen species (ROS). However, the linkage between ROS and insulin resistance in skeletal muscle remains unclear. To explore potential mechanisms, we employed the transgenic TG(mRen2)27 (Ren-2) hypertensive rat, which harbors the mouse renin transgene and exhibits elevated tissue ANG II levels, and skeletal muscle cell culture. Compared with Sprague-Dawley normtensive control rats, Ren-2 skeletal muscle exhibited significantly increased oxidative stress, NF-κB activation, and TNF-α expression, which were attenuated by in vivo treatment with an angiotensin type 1 receptor blocker (valsartan) or SOD/catalase mimetic (tempol). Moreover, ANG II treatment of L6 myotubes induced NF-κB activation and TNF-α production and decreased insulin-stimulated Akt activation and GLUT-4 glucose transporter translocation to plasma membranes. These effects were markedly diminished by treatment of myotubes with valsartan, the antioxidant N-acetylcysteine, NADPH oxidase-inhibiting peptide (gp91 ds-tat), or NF-κB inhibitor (MG-132). Similarly, NF-κB p65 small interfering RNA reduced NF-κB p65 subunit expression and nuclear translocation and TNF-α production but improved insulin-stimulated phosphorylation (Ser473) of Akt and translocation of GLUT-4. These findings suggest that NF-κB plays an important role in ANG II/ROS-induced skeletal muscle insulin resistance.

Original languageEnglish (US)
Pages (from-to)E345-E351
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume294
Issue number2
DOIs
StatePublished - Feb 2008

Keywords

  • Nuclear factor-κB
  • Reactive oxygen species
  • Reduced nicotinamide adenine dinucleotide phosphate
  • Renin-angiotensin system
  • TG(mRen2)27 rat
  • Tumor necrosis factor-α, angiotensin receptor blocker

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

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