Update on new aspects of the renin–angiotensin system in liver disease: clinical implications and new therapeutic options

The RAS (renin–angiotensin system) is now recognized as an important regulator of liver fibrosis and portal pressure. Liver injury stimulates the hepatic expression of components of the RAS, such as ACE (angiotensin-converting enzyme) and the AT1 receptor [AngII (angiotensin II) type 1 receptor], which play an active role in promoting inflammation and deposition of extracellular matrix. In addition, the more recently recognized structural homologue of ACE, ACE2, is also up-regulated. ACE2 catalyses the conversion of AngII into Ang-(1–7) [angiotensin-(1–7)], and there is accumulating evidence that this ‘alternative axis’ of the RAS has anti-fibrotic, vasodilatory and anti-proliferative effects, thus counterbalancing the effects of AngII in the liver. The RAS is also emerging as an important contributor to the pathophysiology of portal hypertension in cirrhosis. Although the intrahepatic circulation in cirrhosis is hypercontractile in response to AngII, resulting in increased hepatic resistance, the splanchnic vasculature is hyporesponsive, promoting the development of the hyperdynamic circulation that characterizes portal hypertension. Both liver fibrosis and portal hypertension represent important therapeutic challenges for the clinician, and there is accumulating evidence that RAS blockade may be beneficial in these circumstances. The present review outlines new aspects of the RAS and explores its role in the pathogenesis and treatment of liver fibrosis and portal hypertension.

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Update on New Aspects of the Renin-Angiotensin System in Hepatic Fibrosis and Portal Hypertension: Implications for Novel Therapeutic Options

Journal of Clinical Medicine ◽

10.3390/jcm10040702 ◽

2021 ◽

Vol 10 (4) ◽

pp. 702

Author(s):

Indu G. Rajapaksha ◽

Lakmie S. Gunarathne ◽

Peter W. Angus ◽

Chandana B. Herath

Keyword(s):

Portal Hypertension ◽

Liver Disease ◽

Animal Models ◽

Liver Fibrosis ◽

Hepatic Fibrosis ◽

Portal Pressure ◽

Renin Angiotensin System ◽

Ang Ii ◽

Angiotensin System ◽

Key Enzyme

There is considerable experimental evidence that the renin angiotensin system (RAS) plays a central role in both hepatic fibrogenesis and portal hypertension. Angiotensin converting enzyme (ACE), a key enzyme of the classical RAS, converts angiotensin I (Ang I) to angiotensin II (Ang II), which acts via the Ang II type 1 receptor (AT1R) to stimulate hepatic fibrosis and increase intrahepatic vascular tone and portal pressure. Inhibitors of the classical RAS, drugs which are widely used in clinical practice in patients with hypertension, have been shown to inhibit liver fibrosis in animal models but their efficacy in human liver disease is yet to be tested in adequately powered clinical trials. Small trials in cirrhotic patients have demonstrated that these drugs may lower portal pressure but produce off-target complications such as systemic hypotension and renal failure. More recently, the alternate RAS, comprising its key enzyme, ACE2, the effector peptide angiotensin-(1–7) (Ang-(1–7)) which mediates its effects via the putative receptor Mas (MasR), has also been implicated in the pathogenesis of liver fibrosis and portal hypertension. This system is activated in both preclinical animal models and human chronic liver disease and it is now well established that the alternate RAS counter-regulates many of the deleterious effects of the ACE-dependent classical RAS. Work from our laboratory has demonstrated that liver-specific ACE2 overexpression reduces hepatic fibrosis and liver perfusion pressure without producing off-target effects. In addition, recent studies suggest that the blockers of the receptors of alternate RAS, such as the MasR and Mas related G protein-coupled receptor type-D (MrgD), increase splanchnic vascular resistance in cirrhotic animals, and thus drugs targeting the alternate RAS may be useful in the treatment of portal hypertension. This review outlines the role of the RAS in liver fibrosis and portal hypertension with a special emphasis on the possible new therapeutic approaches targeting the ACE2-driven alternate RAS.

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UPREGULATION OF RENIN ANGIOTENSIN SYSTEM IN TYPE 1 DIABETES MELLITUS ASSOCIATED WITH HYPERTENSION

Journal of Hypertension ◽

10.1097/00004872-201106001-01112 ◽

2011 ◽

Vol 29 ◽

pp. e377-e378

Author(s):

L. Morais ◽

I. Watanabe ◽

M. Franco ◽

D. Arita ◽

M. Gabbay ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 1 Diabetes ◽

Type 1 Diabetes Mellitus ◽

Renin Angiotensin System ◽

Angiotensin System ◽

Renin Angiotensin

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Erythropoietin during hypoglycaemia in type 1 diabetes: Relation to basal renin-angiotensin system activity and cognitive function

Diabetes Research and Clinical Practice ◽

10.1016/j.diabres.2009.01.008 ◽

2009 ◽

Vol 85 (1) ◽

pp. 75-84 ◽

Cited By ~ 10

Author(s):

Peter Lommer Kristensen ◽

Thomas Høi-Hansen ◽

Niels Vidiendal Olsen ◽

Ulrik Pedersen-Bjergaard ◽

Birger Thorsteinsson

Keyword(s):

Type 1 Diabetes ◽

Cognitive Function ◽

Renin Angiotensin System ◽

Angiotensin System ◽

System Activity ◽

Renin Angiotensin

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Up-regulation of components of the renin–angiotensin system in liver fibrosis in the rat induced by CCL4

Research in Veterinary Science ◽

10.1016/j.rvsc.2013.01.028 ◽

2013 ◽

Vol 95 (1) ◽

pp. 54-58 ◽

Cited By ~ 11

Author(s):

Wei Zhang ◽

JinFeng Miao ◽

PengFei Li ◽

YanXia Wang ◽

YuanShu Zhang

Keyword(s):

Liver Fibrosis ◽

Renin Angiotensin System ◽

Angiotensin System ◽

Renin Angiotensin

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Abstract 227: The Protective Effect of Kidney-Specific ACE Inhibition Against Chronic Angiotensin II Infusions is Associated with Blunted Intrarenal Renin-Angiotensin System Activation

Hypertension ◽

10.1161/hyp.60.suppl_1.a227 ◽

2012 ◽

Vol 60 (suppl_1) ◽

Author(s):

Jorge F Giani ◽

Tea Djandjoulia ◽

Nicholas Fetcher ◽

Sebastien Fuchs ◽

Dale M Seth ◽

...

Keyword(s):

Renin Angiotensin System ◽

Fold Increase ◽

Ace Inhibition ◽

Sham Operation ◽

Ang Ii ◽

Angiotensin System ◽

Renin Angiotensin ◽

Intrarenal Ras ◽

Failed Induction

Introduction: The responses to chronic angiotensin (Ang) II infusions of gene-targeted mice lacking kidney angiotensin-converting enzyme (ACE), in terms of intrarenal Ang II accumulation, hypertension, sodium and water retention are all blunted or absent. The objective of this study was to determine if these reduced responses were associated with changes in the intrarenal renin-angiotensin system (RAS). METHODS: Mice lacking intrarenal ACE (ACE10/10) were generated by targeted homologous recombination placing the expression of ACE only in macrophages. As a result, these mice have normal circulating ACE levels, but no kidney ACE. Wild-type (WT) mice of the same background (C57Bl/J) served as controls. Mice were subjected to sham-operation or subcutaneous infusion of Ang II for two weeks (n=6-10, 400 ng/kg/min via osmotic minipump). Mean arterial pressure (MAP) was followed by telemetry. At the end of the experiment, the kidneys were collected for analysis. Ang II content was measured by RIA. Renal abundance of ACE, angiotensinogen (AGT) and Ang II receptor type 1 (AT1R) were determined by Western Blot in total kidney homogenates. Results: At baseline, the MAP of WT and ACE 10/10 mice was similar 110 ± 4 mmHg vs. 109 ± 3 mmHg respectively (p>0.05). However, when subjected to chronic Ang II infusions, the hypertensive response was blunted in ACE 10/10 mice (129 ± 6 mmHg) vs. WT (146 ± 5 mmHg; P<0.05). Also, intrarenal Ang II accumulation was lower in ACE10/10 mice (724 ± 81 fmol/g) vs. WT (1130 ± 105 fmol/g, p<0.05). In non-treated mice, intrarenal RAS components analysis revealed that the absence of ACE in ACE10/10 mice was accompanied by a significant reduction in AGT (0.41 ± 0.06) and increased AT1R expression (1.32 ± 0.05) when compared to WT (normalized to 1.00, p<0.05 in both instances). Importantly, after chronic Ang II infusions, AGT, ACE and AT1R expression increased in WT (1.36, 1.26 and 1.17 fold increase respectively compared to non-treated WT, p<0.05) but not in the ACE10/10 mice (1.19, 1.06, 0.89 fold increase respectively compared to non-treated ACE10/10, p>0.05). Conclusion: The blunted hypertension and Ang II accumulation of mice devoid of kidney ACE in response to Ang II infusions is associated with a failed induction of renal AGT and the AT1R.

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The role of the renin-angiotensin system and oxidative stress in spontaneously hypertensive rat mesenteric collateral growth impairment

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01296.2006 ◽

2007 ◽

Vol 292 (5) ◽

pp. H2523-H2531 ◽

Cited By ~ 21

Author(s):

Steven J. Miller ◽

Laura E. Norton ◽

Michael P. Murphy ◽

Michael C. Dalsing ◽

Joseph L. Unthank

Keyword(s):

Renin Angiotensin System ◽

Ang Ii ◽

Hypertensive Rats ◽

Angiotensin System ◽

Spontaneously Hypertensive ◽

Renin Angiotensin ◽

Growth Impairment ◽

Collateral Growth ◽

Collateral Artery

Recent clinical and animal studies have shown that collateral artery growth is impaired in the presence of vascular risk factors, including hypertension. Available evidence suggests that angiotensin-converting enzyme inhibitors (ACEI) promote collateral growth in both hypertensive humans and animals; however, the specific mechanisms are not established. This study evaluated the hypothesis that collateral growth impairment in hypertension is mediated by excess superoxide produced by NAD(P)H oxidase in response to stimulation of the ANG II type 1 receptor. After ileal artery ligation, mesenteric collateral growth did not occur in untreated, young, spontaneously hypertensive rats. Significant luminal expansion occurred in collaterals of spontaneously hypertensive rats treated with the superoxide dismutase mimetic tempol, the NAD(P)H oxidase inhibitor apocynin, and the ACEI captopril, but not ANG II type 1 (losartan) or type 2 (PD-123319) receptor blockers. The ACEI enalapril produced equivalent reduction of arterial pressure as captopril but did not promote luminal expansion. This suggests the effects of captopril on collateral growth might result from its antioxidant properties. RT-PCR demonstrated that ANG II type 1 receptor and angiotensinogen expression was reduced in collaterals of untreated rats. This local suppression of the renin angiotensin system provides a potential explanation for the lack of effect of enalapril and losartan on collateral growth. The results demonstrate the capability of antioxidant therapies, including captopril, to reverse impaired collateral artery growth and the novel finding that components of the local renin angiotensin system are naturally suppressed in collaterals.

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Nicotine and the renin-angiotensin system

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00099.2018 ◽

2018 ◽

Vol 315 (5) ◽

pp. R895-R906 ◽

Cited By ~ 88

Author(s):

Joshua M. Oakes ◽

Robert M. Fuchs ◽

Jason D. Gardner ◽

Eric Lazartigues ◽

Xinping Yue

Keyword(s):

Cigarette Smoking ◽

Renin Angiotensin System ◽

Ang Ii ◽

Angiotensin System ◽

Renin Angiotensin ◽

Regulatory Systems ◽

Health And Disease ◽

Former Smokers ◽

New Generation

Cigarette smoking is the single most important risk factor for the development of cardiovascular and pulmonary diseases (CVPD). Although cigarette smoking has been in constant decline since the 1950s, the introduction of e-cigarettes or electronic nicotine delivery systems 10 yr ago has attracted former smokers as well as a new generation of consumers. Nicotine is a highly addictive substance, and it is currently unclear whether e-cigarettes are “safer” than regular cigarettes or whether they have the potential to reverse the health benefits, notably on the cardiopulmonary system, acquired with the decline of tobacco smoking. Of great concern, nicotine inhalation devices are becoming popular among young adults and youths, emphasizing the need for awareness and further study of the potential cardiopulmonary risks of nicotine and associated products. This review focuses on the interaction between nicotine and the renin-angiotensin system (RAS), one of the most important regulatory systems on autonomic, cardiovascular, and pulmonary functions in both health and disease. The literature presented in this review strongly suggests that nicotine alters the homeostasis of the RAS by upregulating the detrimental angiotensin-converting enzyme (ACE)/angiotensin (ANG)-II/ANG II type 1 receptor axis and downregulating the compensatory ACE2/ANG-(1–7)/Mas receptor axis, contributing to the development of CVPD.

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Role of the renin-angiotensin system in liver fibrosis

World Chinese Journal of Digestology ◽

10.11569/wcjd.v21.i22.2151 ◽

2013 ◽

Vol 21 (22) ◽

pp. 2151

Author(s):

Shuang Li

Keyword(s):

Liver Fibrosis ◽

Renin Angiotensin System ◽

Angiotensin System ◽

Renin Angiotensin

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Renin-Angiotensin System Blockers and the COVID-19 Pandemic

Hypertension ◽

10.1161/hypertensionaha.120.15082 ◽

2020 ◽

Vol 75 (6) ◽

pp. 1382-1385 ◽

Cited By ~ 201

Author(s):

A.H. Jan Danser ◽

Murray Epstein ◽

Daniel Batlle

Keyword(s):

Angiotensin Ii ◽

Severe Acute Respiratory Syndrome ◽

Angiotensin Converting Enzyme ◽

Renin Angiotensin System ◽

Converting Enzyme ◽

Angiotensin System ◽

Renin Angiotensin ◽

Receptor Blockers ◽

Renin Angiotensin System Blockers

During the spread of the severe acute respiratory syndrome coronavirus-2, some reports of data still emerging and in need of full analysis indicate that certain groups of patients are at risk of COVID-19. This includes patients with hypertension, heart disease, diabetes mellitus, and clearly the elderly. Many of those patients are treated with renin-angiotensin system blockers. Because the ACE2 (angiotensin-converting enzyme 2) protein is the receptor that facilitates coronavirus entry into cells, the notion has been popularized that treatment with renin-angiotensin system blockers might increase the risk of developing a severe and fatal severe acute respiratory syndrome coronavirus-2 infection. The present article discusses this concept. ACE2 in its full-length form is a membrane-bound enzyme, whereas its shorter (soluble) form circulates in blood at very low levels. As a mono-carboxypeptidase, ACE2 contributes to the degradation of several substrates including angiotensins I and II. ACE (angiotensin-converting enzyme) inhibitors do not inhibit ACE2 because ACE and ACE2 are different enzymes. Although angiotensin II type 1 receptor blockers have been shown to upregulate ACE2 in experimental animals, the evidence is not always consistent and differs among the diverse angiotensin II type 1 receptor blockers and differing organs. Moreover, there are no data to support the notion that ACE inhibitor or angiotensin II type 1 receptor blocker administration facilitates coronavirus entry by increasing ACE2 expression in either animals or humans. Indeed, animal data support elevated ACE2 expression as conferring potential protective pulmonary and cardiovascular effects. In summary, based on the currently available evidence, treatment with renin-angiotensin system blockers should not be discontinued because of concerns with coronavirus infection.

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