Efeitos do tratamento oral com angiotensina-(1-7) no tecido adiposo de camundongos obesos e não obesos jovens, adultos e velhos

Abstract

Aging is a process characterized by cell senescence, and additionally, studies have shown that obesity, an important metabolic disorder, triggers inflammatory processes, insulin resistance, reactive oxygen species activation, among others shared-aging process hallmarks. Growing evidence reveals that the renin-angiotensin system components, including Angiotensin-(1-7), develop beneficial effects on health, preventing and controlling several metabolic disorders derived diseases and aging. In this perspective, we first investigated, via a review, studies regarding the Angiotensin-(1-7) actions on aging-associated conditions and metabolic disorders. Following, we aimed to investigate the Angiotensin-(1-7) effects on young and aged mice fed standard and high-fat diet. Male SWISS mice were divided into twelve groups as follows: (standard diet + cyclodextrin (Ang-(1-7) inclusion compound), standard diet + Ang-(1-7), high-fat diet + cyclodextrin and high-fat diet + Ang-(1-7) (dosage: 30µg/kg/body weight) for 3, 6 and 12 months. The mice body weight, food intake, and lifespan were evaluated during the treatment. At the end of the treatment periods, insulin sensitivity and glucose tolerance tests were performed to evaluate glucose metabolism. Following, the animals were killed by decapitation, and blood samples were collected for biochemical, glycemic and lipid parameters assessment. The epidydimal adipose tissue was removed, and weighted for posterior analysis. Additionally, qRT-PCR was used to validate the bioinformatic analysis, where the AKT1 and IL6 expression levels were assessed. The study was approved by the Committee of Ethics and Experimental Research of the Universidade Estadual de Montes Claros. The results were grouped in two manuscripts. First, the Ang-(1-7) beneficial and protective effects on aging, especially in the cerebrovascular, cardiovascular and renal systems were shown. Studies reporting the Ang-(1-7) effects on metabolic conditions and obesity during aging were scarce in the literature. In the second manuscript, the main findings showed that Ang-(1-7) improves insulin sensitivity, body adiposity, dyslipidemia and modulates the oxidative stress via modulation of DHE, Catalase, TBARs, and GSH. It is worth mentioning that the Ang-(1-7) oral treatment did not significantly affect mice lifespan. To understand the genes and molecular mechanisms related to aging and white adipose tissue and the angiotensins actions, we conducted bioinformatics analysis and identified the main genes involved: AKT1, IL-6, VEGF, and INS. The AKT1 expression levels were increased in aged animals treated with Ang-(1-7), corroborating the bioinformatic findings, while IL6 expression remain unaltered among groups. As far as we know, this is the first study to evidence the Ang-(1-7) oral formulation role during aging in mice and its actions on oxidative stress. We concluded that Ang-(1-7) seems to exert a protective effect by relieving damage on the metabolic regulation mechanisms during aging in the white adipose tissue. Furthermore, additional translational studies, with nanoformulations based on the controlled release of Ang-(1-7), as well studies performed in different aging animal models, are needed for the investigation of additional signaling pathways involved in the Ang-(1-7) effects and the discovery of possible anti-senescence therapies using Ang-(1-7) or analogues.