RGD Reference Report - Angiotensin II-induced skeletal muscle insulin resistance mediated by NF-kappaB activation via NADPH oxidase. - Rat Genome Database

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

Authors: Wei, Y  Sowers, JR  Clark, SE  Li, W  Ferrario, CM  Stump, CS 
Citation: Wei Y, etal., Am J Physiol Endocrinol Metab. 2008 Feb;294(2):E345-51. Epub 2007 Dec 11.
RGD ID: 2298860
Pubmed: PMID:18073321   (View Abstract at PubMed)
DOI: DOI:10.1152/ajpendo.00456.2007   (Journal Full-text)

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 normotensive control rats, Ren-2 skeletal muscle exhibited significantly increased oxidative stress, NF-kappaB activation, and TNF-alpha 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-kappaB activation and TNF-alpha 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-kappaB inhibitor (MG-132). Similarly, NF-kappaB p65 small interfering RNA reduced NF-kappaB p65 subunit expression and nuclear translocation and TNF-alpha production but improved insulin-stimulated phosphorylation (Ser(473)) of Akt and translocation of GLUT-4. These findings suggest that NF-kappaB plays an important role in ANG II/ROS-induced skeletal muscle insulin resistance.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Insulin Resistance  ISORela (Rattus norvegicus)2298860; 2298860protein:altered localization:soleusRGD 
Insulin Resistance  IEP 2298860protein:altered localization:soleusRGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
negative regulation of insulin receptor signaling pathway  IMP 2298860 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Rela  (RELA proto-oncogene, NF-kB subunit)

Genes (Mus musculus)
Rela  (v-rel reticuloendotheliosis viral oncogene homolog A (avian))

Genes (Homo sapiens)
RELA  (RELA proto-oncogene, NF-kB subunit)


Additional Information