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The renin-angiotensin (Ang) system (RAS) is a complex hormonal system present locally in several tissues such as cardiovascular organs. RAS deregulation through overactivation of the classical arm [Ang-converting enzyme (ACE)/Ang-II/Ang type 1 receptor (AT1R)] has been linked to the development of cardiovascular diseases and activation of endoplasmic reticulum (ER) stress pathways. The ER stress is a condition that, if unresolved, might lead to heart failure, atherosclerosis, hypertension, and endothelial dysfunction. Accumulated evidence has shown that the RAS modulates the UPR activation. Several studies reported increased ER stress markers in response to Ang-II treatment, in both in vivo and in vitro models. Evidence has also pointed that targeting the RAS classical arm through RAS blockers, gene silencing or genetic models leads to lower levels of ER stress markers. Few studies demonstrated protective effects of the counter-regulatory arm (ACE-2/Ang-(1-7)/Mas receptor) over ER stress. However, the crosstalk mechanisms between the arms of the RAS and ER stress remain unclear. In this review, we sought to explore the classical arm of the RAS as a key mechanism in UPR activation and to suggest a possible protective role of the counter-regulatory arm in mitigating ER stress., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Endoplasmic reticulum (ER) stress poses a new pathological mechanism for metabolic-associated fatty liver disease (MAFLD). MAFLD treatment has encompassed renin-angiotensin system (RAS) blockers and aerobic exercise training, but their association with hepatic ER stress is not well known. Therefore, we aimed to compare the effects of hepatic RAS modulation by enalapril and/or aerobic exercise training over ER stress in MAFLD caused by a diet-induced obesity model. C57BL/6 mice were fed a standard-chow (CON, n = 10) or a high-fat (HF, n = 40) diet for 8 weeks. HF group was then randomly divided into: HF (n = 10), HF + Enalapril (EN, n = 10), HF + Aerobic exercise training (AET, n = 10), and HF + Enalapril+Aerobic exercise training (EN + AET, n = 10) for 8 more weeks. Body mass (BM) and glucose profile were evaluated. In the liver, ACE and ACE2 activity, morphology, lipid profile, and protein expression of ER stress and metabolic markers were assessed. Both enalapril and aerobic exercise training provided comparable efficacy in improving diet-induced MAFLD through modulation of RAS and ER stress, but the latter was more efficient in improving ER stress, liver damage and metabolism. This is the first study to evaluate pharmacological (enalapril) and non-pharmacological (aerobic exercise training) RAS modulators associated with ER stress in a diet-induced MAFLD model. HF diet led to favoring of the RAS classical arm and increased ER stress through higher expression of the eIF2α pathway. These results could be related to HF diet-associated insulin resistance and upregulation of gluconeogenesis enzymes PEPCK and G6Pase, as well as lipid accumulation through increased lipogenic transcription factor SREBP1c and lower PPARα levels. Enalapril treatment, aerobic exercise training, and the combination of both interventions were able to favor the RAS counterregulatory arm, improve ER stress and decrease lipid accumulation. All interventions were also able to improve insulin resistance, although aerobic exercise training showed more efficiency, reverting glucose intolerance and decreasing the expression of PEPCK. Aerobic exercise training was also the only intervention able to reduce binucleation of hepatocytes and the association with enalapril treatment reverted the increase in hepatocytes with two or more nuclei, which could be suggestive of liver damage associated with the pharmacological treatment. [Display omitted] • Enalapril and aerobic exercise training decrease ACE/ACE2 ratio in obese mice. • RAS counterregulatory arm could be associated to decreased ER stress markers in MAFLD. • Aerobic exercise training better improved liver ER stress markers, metabolism and damage. [ABSTRACT FROM AUTHOR]