Abstract
Angiotensin 1-7 (Ang 1-7) enhances insulin signaling and glucose transport activity in the skeletal muscle. The aim of our study was to evaluate the effect of AVE0991, a nonpeptide Mas receptor agonist, on the metabolic parameters, expression of RAS components and markers of oxidative stress, and insulin signaling in the skeletal morbidly obese rats. 33-week-old male obese Zucker rats were treated with vehicle and AVE0991 (0.5 mg/kg BW/day) via osmotic minipumps for two weeks. Gene expressions were determined by qPCR and/or Western blot analysis in musculus quadriceps. The enzymatic activities were detected flourometrically (aminopeptidase A) or by colorimetric assay kit (protein tyrosine phosphatase 1B). Administration of AVE0991 enhanced insulin signaling cascade in the skeletal muscle, reflected by improved whole-body glucose tolerance. It has been shown that reactive oxygen species (ROS) have insulin-mimetic action in muscle. The expression of renin receptor, transcription factor PLZF, and prooxidant genes was upregulated by AVE0991 accompanied by elevated expression of genes coding enzymes with antioxidant action. Our results show that AVE0991 administration activates genes involved in both ROS generation and clearance establishing a new prooxidant/antioxidant balance on a higher level, which might contribute to the improved insulin signaling pathway and glucose tolerance of obese Zucker rats.
Highlights
The renin-angiotensin system (RAS) is well known as an essential regulator of systemic blood pressure as well as fluid and electrolyte homeostasis
The aim of our study was to evaluate the effect of AVE0991 application on the (i) metabolic parameters, (ii) expression of the RAS components and (iii) markers of oxidative stress, and (iv) insulin signaling in the skeletal muscle of obese Zucker rats
Our results indicate that the improvement of insulin signaling cascade occurred via inhibition of insulin receptor substrate 1 (IRS1) serine phosphorylation rather than by increased tyrosine kinase activity in the skeletal muscle
Summary
The renin-angiotensin system (RAS) is well known as an essential regulator of systemic blood pressure as well as fluid and electrolyte homeostasis. Local RAS in the skeletal muscle responds to physiological stimuli; it is capable of de novo angiotensin II (Ang II) production and can function independently of systemic RAS. Ang II has long been considered to be the single critical product of the RAS, which acts via two types of receptors: AT1 and AT2. Most of Ang II effects are mediated by the AT1 receptor, including vasoconstriction, hypertrophy, and cellular growth. Ang 1-7 acts via a Mas receptor and has antagonistic effects to the classical RAS pathway; it is able to improve insulin signaling and glucose transport activity in the skeletal muscle by Oxidative Medicine and Cellular Longevity enhanced insulin receptor substrate 1 (IRS1) and Akt kinase phosphorylation [1, 2]. The effect of AVE0991 on the physiology of skeletal muscle has not been examined yet
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