Skeletal muscle insulin resistance in salt-sensitive hypertension: role of angiotensin II activation of NFκB

Abstract

BackgroundWe have previously shown that in hypertensive Dahl salt-sensitive (DS) rats, impaired endothelium-dependent relaxation to acetylcholine and to insulin is mechanistically linked to up-regulation of angiotensin (Ang) II actions and the production of reactive oxygen species (ROS) and to activation of the proinflammatory transcription factor (NF)κB. Here we investigated whether Ang II activation of NFκB contributed to insulin resistance in the skeletal muscle of this animal model.MethodsDS rats were fed either a normal (NS, 0.5% NaCl) or high (HS, 4% NaCl) salt diet for 6 weeks. In addition, 3 separate groups of HS rats were given angiotensin receptor 1 blocker candesartan (ARB, 10 mg/kg/day in drinking water), antioxidant tempol (1 mmol/L in drinking water) or NFκB inhibitor PDTC (150 mg/kg in drinking water).ResultsDS rats manifested an increase in soleus muscle Ang II content, ROS production and phosopho-IκBα/IκBα ratio, ARB or tempol reduced ROS and phospho-IκBα/IκBα ratio. Hypertensive DS rats also manifested a reduction in glucose infusion rate, impaired insulin-induced Akt phosphorylation and Glut-4 translocation in the soleus muscle, which were prevented with treatment of either ARB, tempol, or PDTC. Data from the rat diabetes signaling pathway PCR array showed that 8 genes among 84 target genes were altered in the muscle of hypertensive rats with the increase in gene expression of ACE1 and 5 proinflammatory genes, and decrease of 2 glucose metabolic genes. Incubation of the muscle with NFκB SN50 (a specific peptide inhibitor of NFκB) ex vivo reversed changes in hypertension-induced gene expression.ConclusionThe current findings strongly suggest that the activation of NFκB inflammatory pathway by Ang II play a critical role in skeletal muscle insulin resistance in salt-sensitive hypertension.

Tissue Sodium Content and Arterial Hypertension in Obese Adolescents

“…In 11 maintenance haemodialysis patients, higher muscle sodium content was, in a similar way, associated with insulin resistance [34]. Furthermore, in the soleus muscle of salt-sensitive hypertensive Dahl rats, the RAAS was shown to activate the NF-κB pro-inflammatory pathway, inducing moderate hyperinsulinemia and insulin resistance [33]. A recent study also demonstrated a positive statistical correlation between Na + intake and insulin resistance in obese children and adolescents [35].…”

“…Insulin alone has long been thought to cause Na + retention, with enough effects to contribute to arterial hypertension [32,33]. A study by Brands and colleagues showed that such Na + -retaining effects may be limited to uncontrolled Type II diabetes [32].…”

Foetal programming by methyl donor deficiency produces steato-hepatitis in rats exposed to high fat diet

“…Furthermore, it improves the contraction and proliferation of myofibroblasts and promotes the release of inflammatory and pro-fibrotic cytokines, including TGF-β1, and the deposition of extracellular matrix30. The activation of NFκB inflammatory pathway by angiotensin plays also a critical role in insulin resistance of rats subjected to HF31. The deleterious angiotensin-AT1 axis impairs glucose homeostasis and favours insulin resistance.…”

Protective effect of pretreatment with propofol against tumor necrosis factor-α-induced hepatic insulin resistance

“…The transcription factor plays an important role in cell signal transduction and gene expression regulation, and is also the critical nuclear factor involved in the initiation and regulation of inflammation. In recent years, the inflammatory response mediated by NF-κB is one focus of research into the mechanisms underlying insulin resistance (30,31). Following NF-κB activation, the transcription of inflammatory factors, such as TNF-α, interleukin (IL)-1β and IL-6, is initiated and regulated.…”