Antioxidant Effects of Oral Ang-(1-7) Restore Insulin Pathway and RAS Components Ameliorating Cardiometabolic Disturbances in Rats

Abstract

In prevention studies of metabolic syndrome (MetS), Ang-(1-7) has shown to improve the insulin signaling. We evaluated the HPβCD/Ang-(1-7) treatment on lipid metabolism, renin-angiotensin system (RAS) components, oxidative stress, and insulin pathway in the liver and gastrocnemius muscle and hepatic steatosis in rats with established MetS. After 7 weeks of high-fat (FAT) or control (CT) diets, rats were treated with cyclodextrin (HPβCD) or HPβCD/Ang-(1-7) in the last 6 weeks. FAT-HPβCD/empty rats showed increased adiposity index and body mass, gene expression of ACE/ANG II/AT1R axis, and oxidative stress. These results were accompanied by imbalances in the insulin pathway, worsening of liver function, hyperglycemia, and dyslipidemia. Oral HPβCD/Ang-(1-7) treatment decreased ACE and AT1R, increased ACE2 gene expression in the liver, and restored thiobarbituric acid reactive substances (TBARS), catalase (CAT), superoxide dismutase (SOD), insulin receptor substrate (Irs-1), glucose transporter type 4 (GLUT4), and serine/threonine kinase 2 (AKT-2) gene expression in the liver and gastrocnemius muscle improving hepatic function, cholesterol levels, and hyperglycemia in MetS rats. Overall, HPβCD/Ang-(1-7) treatment restored the RAS components, oxidative stress, and insulin signaling in the liver and gastrocnemius muscle contributing to the establishment of blood glucose and lipid homeostasis in MetS rats.

Metabolic Dysregulation in Idiopathic Pulmonary Fibrosis

“…Plasma levels of ANGT are reported to be modulated by hormones such as corticosteroid, oestrogen, thyroid hormones and angiotensin II [ 46 , 47 ], suggesting that hormone imbalance could influence RAAS and its dysregulation. The important role of RAAS in metabolic regulation is also explained by its two axes: ACE-2/Ang 1–7/Mas which has antiproliferative, antioxidant and anti-inflammatory functions with beneficial effects on hypertension, glucose intolerance and insulin resistance (IR); and the counter-regulatory ACE/Ang II/AT1 [ 48 ] with opposite effects. ACE-2 has been shown to play a protective role in lung disease through effects mediated by the Mas oncogene.…”

“…In the lung of IPF patients, ACE-2 is reported to be significantly depleted [ 49 ], suggesting that RAAS is important in the pathogenesis of IPF. In turn, the dysregulation of RAAS components can trigger many metabolic functions, such as those observed in metabolic syndrome and diabetes mellitus type 2 [ 48 ]. Indeed, in diabetic retinopathy, RAAS is an effector of vascular epithelial growth factor (VEGF) that drive the leakage of retinal blood vessels [ 50 ].…”

BPA disrupts 17‑estradiol‑mediated hepatic protection against ischemia/reperfusion injury in rat liver by upregulating the Ang�II/AT1R signaling pathway

“…However, compared with aT1r, it is difficult to investigate the functions of AT2R, at least in part due to the relatively low expression levels in cells (23). Previous studies investigating ang ii and its receptors have primarily focused on the ang ii/aT1r axis (24)(25)(26)(27); therefore, the present study investigated the effects of BPa on hepatic damage and the ang ii/aT1r signaling pathway in a rat model of liver i/r injury. a previous study reported that 0.4 mg/kg/day BPa in rats is close to the current reference daily limit for human exposure by the u.S. environmental Protection agency (28).…”

The Novel Angiotensin-(1–7) Analog, A-1317, Improves Insulin Resistance by Restoring Pancreatic β-Cell Functionality in Rats With Metabolic Syndrome

“…In prevention studies, oral administration of Ang-(1–7) improved body mass, adiposity index, plasma triglycerides levels, glucose tolerance, insulin sensitivity in rats and mice fed with HF ( Oliveira Andrade et al, 2014 ; Williams et al, 2016 ) and fructose ( Giani et al, 2009 ; Muñoz et al, 2012 ) diets. Additionally, in recent studies ( Barbosa et al, 2019 ; Figueiredo et al, 2019 ) we have shown that oral treatment with Ang-(1–7) in rats, with established MetS induced by HF diet, was effective in restoring biometric, biochemical parameters, redox process, and RAS components in the liver and gastrocnemic muscle ( Figueiredo et al, 2019 ). Also, oral treatment with Ang-(1–7) was able to remodel the white and brown adipose tissue ( Barbosa et al, 2019 ).…”

“…These disorders are related to redox imbalance resulting in higher formation of reactive oxygen species such as superoxide and hydroxyl radicals, which can lead to mitochondrial dysfunction and accumulation of oxidized proteins and lipids ( Estadella et al, 2013 ; Peluso et al, 2017 ; Zacarias et al, 2017 ; Vona et al, 2019 ). In addition, HF diet induces liver damage related to various disorders occurring in the MetS such as IR, dyslipidemia, and increased adiposity ( Rosselli et al, 2014 ; Zacarias et al, 2017 ; Barbosa et al, 2019 ; Figueiredo et al, 2019 ). Additionally, in pancreatic b -cells, different concentrations of nitric oxide (NO) exerts positive or negative regulation of insulin secretion ( Meares et al, 2011 ) and thus improving or worsening the state of IR ( Kaneko and Ishikawa, 2013 ).…”