The role of renin-angiotensin system modulation on treatment and prevention of liver diseases

Macêdo, Simone Moreira de; Guimarães, Talita Antunes; Feltenberger, John David; Santos, Sérgio Henrique Sousa

doi:10.1016/j.peptides.2014.10.005

Cited by 86 publications

(71 citation statements)

References 92 publications

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“…This oral treatment has reduced liver weight and steatosis, total plasma cholesterol, triglyceride, and alaninetransaminase enzyme levels. Also, oral treatment with Ang-(1-7) was able to prevent and treat liver fat deposition in obese mice and rats [70].…”

Section: Alternative Ras Signaling and Liver Diseasesmentioning

confidence: 98%

Role of renin-angiotensin system in liver diseases: an outline on the potential therapeutic points of intervention

Ahmadian

Pennefather

Eftekhari

et al. 2016

Expert Review of Gastroenterology & Hepatology

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The current review aimed to outline the functions of the renin angiotensin system (RAS) in the context of the oxidative stress-associated liver disease. Areas covered: Angiotensin II (Ang II) as the major effector peptide of the RAS is a pro-oxidant and fibrogenic cytokine. Mechanistically, NADPH oxidase (NOX) is a multicomponent enzyme complex that is able to generate reactive oxygen species (ROS) as a downstream signaling pathway of Ang II which is expressed in liver. Ang II has a detrimental role in the pathogenesis of chronic liver disease through possessing pro-oxidant, fibrogenic, and pro-inflammatory impact in the liver. The alternative axis (ACE2/Ang(1-7)/mas) of the RAS serves as an anti-inflammatory, antioxidant and anti-fibrotic component of the RAS. Expert commentary: In summary, the use of alternative axis inhibitors accompanying with ACE2/ Ang(1-7)/mas axis activation is a promising new strategy serving as a novel therapeutic option to prevent and treat chronic liver diseases.

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Section: Alternative Ras Signaling and Liver Diseasesmentioning

confidence: 98%

Role of renin-angiotensin system in liver diseases: an outline on the potential therapeutic points of intervention

Ahmadian

Pennefather

Eftekhari

et al. 2016

Expert Review of Gastroenterology & Hepatology

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“…Bearing this in mind, the angiotensin receptor blockers (ARBs) represents an evolution of the ACE inhibitors as they block exclusively the actions mediate by the interaction of ANG II with the AT1R[19,20]. Thus, important physiological effects stemmed from ANG II interaction with AT2R are maintained, leading to reduced atherogenesis, greater cardiac and endocrine pancreas functions, reduced glomerulosclerosis and fatty liver[21,22]. …”

Section: Circulating Rasmentioning

confidence: 99%

“…These conditions comply with the increase of de novo lipogenesis (the formation of fatty acids from excessive dietary carbohydrate)[27,31]. Concomitantly, the increased production of reactive oxygen species by mitochondria and the raised expression of pro-inflammatory cytokines contribute to the progression to NASH[22]. These effects are mainly mediated by higher expression of ACE, ANG II, and AT1R concomitant to reduced ACE2 tissue expression in the hepatocytes of obese mice[32].…”

Section: Local Ras: Hepatic Effectsmentioning

confidence: 99%

Hepatic structural enhancement and insulin resistance amelioration due to AT1 receptor blockade

Souza-Mello

2017

WJH

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Over the last decade, the role of renin-angiotensin system (RAS) on the development of obesity and its comorbidities has been extensively addressed. Both circulating and local RAS components are up-regulated in obesity and involved in non-alcoholic fatty liver disease onset. Pharmacological manipulations of RAS are viable strategies to tackle metabolic impairments caused by the excessive body fat mass. Renin inhibitors rescue insulin resistance, but do not have marked effects on hepatic steatosis. However, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ARB) yield beneficial hepatic remodeling. ARBs elicit body mass loss and normalize insulin levels, tackling insulin resistance. Also, this drug class increases adiponectin levels, besides countering interleukin-6, tumoral necrosis factor-alpha, and transforming growth factor-beta 1. The latter is essential to prevent from liver fibrosis. When conjugated with peroxisome proliferator-activated receptor (PPAR)-alpha activation, ARB fully rescues fatty liver. These effects might be orchestrated by an indirect up-regulation of MAS receptor due to angiotensin II receptor type 1 (AT1R) blockade. These associations of ARB with PPAR activation and ACE2-angiotensin (ANG) (1-7)-MAS receptor axis deserve a better understanding. This editorial provides a brief overview of the current knowledge regarding AT1R blockade effects on sensitivity to insulin and hepatic structural alterations as well as the intersections of AT1R blockade with peroxisome proliferator-activated receptor activation and ACE2-ANG (1-7) - MAS receptor axis.

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“…Renin converts angiotensinogen into angiotensin I (Ang I), which is then converted to angiotensin II (Ang II) by angiotensin-converting enzyme (ACE). Ang II mediates biological responses through Ang II receptor type 1 (AT1) and Ang II receptor type 2 (AT2), but AT1 is the main receptor that mediates the biological effects of Ang II (Moreira de Macedo et al 2014). Ang II is a proinflammatory, pro-oxidant, and pro-thrombotic protein that interferes with the insulin signaling.…”

Section: Angiotensin and Related Blocking Agentsmentioning

confidence: 99%

“…Previous studies have indicated that both the ACE and AT1 genes are upregulated in areas of active hepatic fibrogenesis, and Ang II induces the activation and proliferation of HSCs through AT1. The anti-fibrotic effect of Ang II blocking agents has been shown in various animal models and hepatitis C patients, suggesting ACE/Ang II/AT1 could be a promising target for liver fibrosis therapy (Moreira de Macedo et al 2014). A recent clinical study of the long-term oral administration of losartan in HCV patients with mild fibrosis showed that losartan treatment was associated with a significant decrease in the expression of procollagen I, IV, urokinase-type plasminogen activator, MMP-2, NOX activator 1 (NOXA-1) and organizer 1 (NOXO-1), and Rac-1.…”

Section: Angiotensin and Related Blocking Agentsmentioning

confidence: 99%

Strategies to prevent and reverse liver fibrosis in humans and laboratory animals

Chen

Wang

2015

Arch Toxicol

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Liver fibrosis results from chronic damage to the liver in conjunction with various pathways and is mediated by a complex microenvironment. Based on clinical observations, it is now evident that fibrosis is a dynamic, bidirectional process with an inherent capacity for recovery and remodeling. The major mechanisms involved in liver fibrosis include the repetitive injury of hepatocytes, the activation of the inflammatory response after injury stimulation, and the activation and proliferation of hepatic stellate cells (HSCs), which represents the major extracellular matrix (ECM)-producing cells, stimulated by hepatocyte injury and inflammation. The microenvironment in the liver is synergistically regulated abnormal ECM deposition, scar formation, angiogenesis, and fibrogenesis. Moreover, recent studies have clarified novel mechanism in fibrosis such as epigenetic regulation of HSCs, the leptin and PPARγ pathways, the coagulation system, and even autophagy. Uncovering the mechanisms of liver fibrogenesis provides a basis to develop potential therapies to reverse and treat the fibrotic response, thereby improving the outcomes of patients with chronic liver disease. Although both scientific and clinical challenges remain, emerging studies attempt to reveal the ideal anti-fibrotic drug that could be easily delivered to the liver with high specificity and low toxicity. This review highlights the mechanisms, including novel pathways underlying fibrogenesis that may be translated into preventive and treatment strategies, reviews both current and novel agents that target specific pathways or multiple targets, and discusses novel drug delivery systems such as nanotechnology that can be applied in the treatment of liver fibrosis. In addition, we also discuss some current treatment strategies that are being applied in animal models and in clinical trials.

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The role of renin-angiotensin system modulation on treatment and prevention of liver diseases

Cited by 86 publications

References 92 publications

Role of renin-angiotensin system in liver diseases: an outline on the potential therapeutic points of intervention

Role of renin-angiotensin system in liver diseases: an outline on the potential therapeutic points of intervention

Hepatic structural enhancement and insulin resistance amelioration due to AT1 receptor blockade

Strategies to prevent and reverse liver fibrosis in humans and laboratory animals

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