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

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.

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

2012 ◽  
Vol 123 (4) ◽  
pp. 225-239 ◽  
Author(s):  
Josephine A. Grace ◽  
Chandana B. Herath ◽  
Kai Yan Mak ◽  
Louise M. Burrell ◽  
Peter W. Angus
Keyword(s):  
Portal Hypertension ◽  
Liver Fibrosis ◽  
Portal Pressure ◽  
Renin Angiotensin System ◽  
Active Role ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Hepatic Expression ◽  
Important Regulator

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.

scholarly journals Activation of the Alternate Renin-Angiotensin System Correlates with the Clinical Status in Human Cirrhosis and Corrects Post Liver Transplantation

2019 ◽  
Vol 8 (4) ◽  
pp. 419 ◽  
Author(s):  
Stephen Casey ◽  
Robert Schierwagen ◽  
Kai Mak ◽  
Sabine Klein ◽  
Frank Uschner ◽  
...  
Keyword(s):  
Liver Transplantation ◽  
Liver Disease ◽  
Animal Studies ◽  
Clinical Status ◽  
Renin Angiotensin System ◽  
Blood Sampling ◽  
Ang Ii ◽  
Post Transplantation ◽  
Angiotensin System ◽  
Renin Angiotensin

Introduction: Recent animal studies have shown that the alternate renin-angiotensin system (RAS) consisting of angiotensin-converting enzyme 2 (ACE2), angiotensin-(1–7) (Ang-(1–7)) and the Mas receptor is upregulated in cirrhosis and contributes to splanchnic vasodilatation and portal hypertension. To determine the potential relevance of these findings to human liver disease, we evaluated its expression and relationship to the patients’ clinical status in subjects with cirrhosis. Methods: Blood sampling from peripheral and central vascular beds was performed intra-operatively for cirrhotic patients at the time of liver transplantation (LT) or trans-jugular intra-hepatic portosystemic shunt (TIPS) procedures to measure angiotensin II (Ang II) and Ang-(1–7) peptide levels and ACE and ACE2 enzyme activity. Relevant clinical and hemodynamic data were recorded pre-operatively for all subjects and peripheral blood sampling was repeated 3 months or later post-operatively. Results: Ang-(1–-7) and ACE2 activity were up-regulated more than twofold in cirrhotic subjects both at the time of LT and TIPS and levels returned to comparable levels as control subjects post-transplantation. Ang-(1–7) levels correlated positively with the degree of liver disease severity, as measured by the model for an end-stage liver disease (MELD) and also with clinical parameters of pathological vasodilatation including cardiac output (CO). There were strong correlations found between the ACE2:ACE and the Ang-(1–7):Ang II ratio highlighting the inter-dependence of the alternate and classical arms of the RAS and thus their potential impact on vascular tone. Conclusions: In human cirrhosis, the alternate RAS is markedly upregulated and the activation of this system is associated strongly with features of the hyperdynamic circulation in advanced human cirrhosis.

Urotensin II modulates hepatic fibrosis and portal hemodynamic alterations in rats

2009 ◽  
Vol 297 (4) ◽  
pp. G762-G767 ◽  
Author(s):  
William Kemp ◽  
Andrew Kompa ◽  
Arintaya Phrommintikul ◽  
Chandana Herath ◽  
Jia Zhiyuan ◽  
...  
Keyword(s):  
Portal Hypertension ◽  
Liver Disease ◽  
Growth Factor ◽  
Hepatic Fibrosis ◽  
Transforming Growth Factor ◽  
Venous Pressure ◽  
Portal Pressure ◽  
Hepatic Tissue ◽  
High Dose ◽  
Urotensin Ii

The influence of circulating urotensin II (UII) on liver disease and portal hypertension is unknown. We aimed to evaluate whether UII executes a pathogenetic role in the development of hepatic fibrosis and portal hypertension. UII was administered by continuous infusion over 4 wk in 20 healthy rats divided into three treatment groups, controls (saline, n = 7), low dose (UII, 1 nmol·kg−1·h−1, n = 8), and high dose (UII, 3 nmol·kg−1·h−1, n = 5). Hemodynamic parameters and morphometric quantification of fibrosis were assessed, and profibrotic cytokines and fibrosis markers were assayed in hepatic tissue. UII induced a significant dose-dependent increase in portal venous pressure (5.8 ± 0.4, 6.4 ± 0.3, and 7.6 ± 0.7, respectively, P = 0.03). High-dose UII infusion was associated with an increase in hepatic transcript for transforming growth factor-β ( P < 0.05) and platelet-derived growth factor-β ( P = 0.06). Liver tissue hydroxyproline was elevated in the high-dose group ( P < 0.05). No systemic hemodynamic alterations were noted. We concluded that UII infusion elevates portal pressure and induces hepatic fibrosis in normal rats. This response may be mediated via induction of fibrogenic cytokines. These findings have pathophysiological implications in human liver disease where increased plasma UII levels have been observed.

Renin–angiotensin system inhibition ameliorates CCl4-induced liver fibrosis in mice through the inactivation of nuclear transcription factor kappa B

2018 ◽  
Vol 96 (6) ◽  
pp. 569-576 ◽  
Author(s):  
Sameh Saber ◽  
Amr A.A. Mahmoud ◽  
Noha S. Helal ◽  
Eman El-Ahwany ◽  
Rasha H. Abdelghany
Keyword(s):  
Transcription Factor ◽  
Liver Fibrosis ◽  
Hepatic Fibrosis ◽  
Smooth Muscle Actin ◽  
Renin Angiotensin System ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Nuclear Transcription Factor ◽  
Ras Inhibitors

Therapeutic interventions for liver fibrosis are still limited due to the complicated molecular pathogenesis. Renin–angiotensin system (RAS) seems to contribute to the development of hepatic fibrosis. Therefore, we aimed to examine the effect of RAS inhibition on CCl4-induced liver fibrosis. Mice were treated with silymarin (30 mg·kg−1), perindopril (1 mg·kg−1), fosinopril (2 mg·kg−1), or losartan (10 mg·kg−1). The administration of RAS inhibitors improved liver histology and decreased protein expression of alpha smooth muscle actin (α-SMA) and hepatic content of hydroxyproline. These effects found to be mediated via inactivation of nuclear transcription factor kappa B (NFκB) pathway by the inhibition of NFκB p65 phosphorylation at the Ser536 residue and phosphorylation-induced degradation of nuclear factor kappa-B inhibitor alpha (NFκBia) subsequently inhibited NFκB-induced TNF-α and TGF-β1, leading to lower levels of tissue inhibitor of metalloproteinase-1 (TIMP-1) and vascular endothelial growth factor (VEGF). We concluded that the tissue affinity of the angiotensin converting enzyme inhibitors (ACEIs) has no impact on its antifibrotic activity and that interfering the RAS either through the inhibition of ACE or the blockade of AT1R has the same therapeutic benefit. These results suggest RAS inhibitors as promising candidates for further clinical trials in the management of hepatic fibrosis.

scholarly journals Role of the renin-angiotensin system in hepatic fibrosis and portal hypertension

2018 ◽  
Vol 33 (3) ◽  
pp. 453-461 ◽  
Author(s):  
Kwang Yong Shim ◽  
Young Woo Eom ◽  
Moon Young Kim ◽  
Seong Hee Kang ◽  
Soon Koo Baik
Keyword(s):  
Portal Hypertension ◽  
Hepatic Fibrosis ◽  
Renin Angiotensin System ◽  
Angiotensin System ◽  
Renin Angiotensin

scholarly journals Prognostic Value of Liver and Spleen Stiffness in Patients with Fontan Associated Liver Disease (FALD): A Case Series with Histopathologic Comparison

2021 ◽  
Vol 8 (3) ◽  
pp. 30
Author(s):  
Massimo Padalino ◽  
Liliana Chemello ◽  
Luisa Cavalletto ◽  
Annalisa Angelini ◽  
Marny Fedrigo
Keyword(s):  
Portal Hypertension ◽  
Liver Disease ◽  
Liver Fibrosis ◽  
Prognostic Value ◽  
Fontan Operation ◽  
Vena Cava ◽  
Case Series ◽  
Morbidity And Mortality ◽  
Post Mortem ◽  
Spleen Stiffness

The Fontan operation is the current surgical procedure to treat single-ventricle congenital heart disease, by splitting the systemic and pulmonary circulations and thus permitting lifespan to adulthood for the majority of newborns. However, emerging data are showing that Fontan-associated liver disease (FALD) is an increasing related cause of morbidity and mortality in patients with the Fontan circuit. We described the clinical, laboratory, and transient elastography (TE) findings in a case series of adults with the Fontan circuit, and also correlated data with post-mortem histological features, aimed to define the prognostic value of TE in the staging of FALD. All patients presented signs of a long-standing Fontan failure, characterized by reoperation need, systemic ventricle dysfunction, and FALD stigmata (liver and spleen enlargement, portal vein and inferior vena cava dilation, and abnormal liver function tests). Liver and spleen stiffness (LS and SS) values were indicative of significant liver fibrosis/cirrhosis and the presence of suggestive portal hypertension (LS mean 35.9; range 27.3–44.7 kPa; SS mean 42.1, range 32.2–54.5 kPa). Post-mortem evaluations confirmed a gross hepatic architecture distortion in all cases. All patients died from severe complications related to liver dysfunction and bleeding. TE correlated well with pathological findings and FALD severity. We propose this validated and harmless technique to monitor liver fibrosis extension and portal hypertension over time in Fontan patients, and to identify the optimal timing for surgical reoperations or orthotopic-heart transplantation (OHT), avoiding a higher risk of morbidity and mortality in cases with severe FALD.

scholarly journals A novel role for miR-133a in centrally mediated activation of the renin-angiotensin system in congestive heart failure

2017 ◽  
Vol 312 (5) ◽  
pp. H968-H979 ◽  
Author(s):  
Neeru M. Sharma ◽  
Shyam S. Nandi ◽  
Hong Zheng ◽  
Paras K. Mishra ◽  
Kaushik P. Patel
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Paraventricular Nucleus ◽  
Renin Angiotensin System ◽  
Luciferase Reporter ◽  
Mrna Levels ◽  
Ang Ii ◽  
Angiotensin System ◽  
Renin Angiotensin

An activated renin-angiotensin system (RAS) within the central nervous system has been implicated in sympathoexcitation during various disease conditions including congestive heart failure (CHF). In particular, activation of the RAS in the paraventricular nucleus (PVN) of the hypothalamus has been recognized to augment sympathoexcitation in CHF. We observed a 2.6-fold increase in angiotensinogen (AGT) in the PVN of CHF. To elucidate the molecular mechanism for increased expression of AGT, we performed in silico analysis of the 3′-untranslated region (3′-UTR) of AGT and found a potential binding site for microRNA (miR)-133a. We hypothesized that decreased miR-133a might contribute to increased AGT in the PVN of CHF rats. Overexpression of miR-133a in NG108 cells resulted in 1.4- and 1.5-fold decreases in AGT and angiotensin type II (ANG II) type 1 receptor (AT1R) mRNA levels, respectively. A luciferase reporter assay performed on NG108 cells confirmed miR-133a binding to the 3′-UTR of AGT. Consistent with these in vitro data, we observed a 1.9-fold decrease in miR-133a expression with a concomitant increase in AGT and AT1R expression within the PVN of CHF rats. Furthermore, restoring the levels of miR-133a within the PVN of CHF rats with viral transduction resulted in a significant reduction of AGT (1.4-fold) and AT1R (1.5-fold) levels with a concomitant decrease in basal renal sympathetic nerve activity (RSNA). Restoration of miR-133a also abrogated the enhanced RSNA responses to microinjected ANG II within the PVN of CHF rats. These results reveal a novel and potentially unique role for miR-133a in the regulation of ANG II within the PVN of CHF rats, which may potentially contribute to the commonly observed sympathoexcitation in CHF. NEW & NOTEWORTHY Angiotensinogen (AGT) expression is upregulated in the paraventricular nucleus of the hypothalamus through posttranscriptional mechanism interceded by microRNA-133a in heart failure. Understanding the mechanism of increased expression of AGT in pathological conditions leading to increased sympathoexcitation may provide the basis for the possible development of new therapeutic agents with enhanced specificity.

scholarly journals Intracrine angiotensin II functions originate from noncanonical pathways in the human heart

2016 ◽  
Vol 311 (2) ◽  
pp. H404-H414 ◽  
Author(s):  
Carlos M. Ferrario ◽  
Sarfaraz Ahmad ◽  
Jasmina Varagic ◽  
Che Ping Cheng ◽  
Leanne Groban ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Functional Significance ◽  
Vascular Remodeling ◽  
Human Heart ◽  
Renin Angiotensin System ◽  
Ang Ii ◽  
Extended Form ◽  
Angiotensin I ◽  
Angiotensin System ◽  
Ras Genes

Although it is well-known that excess renin angiotensin system (RAS) activity contributes to the pathophysiology of cardiac and vascular disease, tissue-based expression of RAS genes has given rise to the possibility that intracellularly produced angiotensin II (Ang II) may be a critical contributor to disease processes. An extended form of angiotensin I (Ang I), the dodecapeptide angiotensin-(1–12) [Ang-(1–12)], that generates Ang II directly from chymase, particularly in the human heart, reinforces the possibility that an alternative noncanonical renin independent pathway for Ang II formation may be important in explaining the mechanisms by which the hormone contributes to adverse cardiac and vascular remodeling. This review summarizes the work that has been done in evaluating the functional significance of Ang-(1–12) and how this substrate generated from angiotensinogen by a yet to be identified enzyme enhances knowledge about Ang II pathological actions.

Brain angiotensin system: a new promise in the management of epilepsy?

2021 ◽  
Vol 135 (6) ◽  
pp. 725-730
Author(s):  
Alberto Javier Ramos
Keyword(s):  
Therapeutic Potential ◽  
Renin Angiotensin System ◽  
B Cell Lymphoma ◽  
Ang Ii ◽  
Angiotensin System ◽  
Beneficial Effects ◽  
System A ◽  
Pilocarpine Model ◽  
Animal Models Of Epilepsy ◽  
Future Work

Abstract Epilepsy is a highly prevalent neurological disease and anti-epileptic drugs (AED) are almost the unique clinical treatment option. A disbalanced brain renin–angiotensin system (RAS) has been proposed in epilepsy and several reports have shown that angiotensin II (Ang II) receptor-1 (ATR1) activation is pro-inflammatory and pro-epileptogenic. In agreement, ATR1 blockage with the repurposed drug losartan has shown benefits in animal models of epilepsy. Processing of Ang II by ACE2 enzyme renders Ang-(1-7), a metabolite that activates the mitochondrial assembly (Mas) receptor (MasR) pathway. MasR activation presents beneficial effects, facilitating vasodilatation, increasing anti-inflammatory and antioxidative responses. In a recent paper published in Clinical Science, Gomes and colleagues (Clin. Sci. (Lond.) (2020) 134, 2263–2277) performed intracerebroventricular (icv) infusion of Ang-(1-7) in animals subjected to the pilocarpine model of epilepsy, starting after the first spontaneous motor seizure (SMS). They showed that this approach reduced the frequency of SMS, restored animal anxiety, increased exploration, and augmented the hippocampal expression of protective catalase enzyme and antiapoptotic protein B-cell lymphoma 2 (Bcl-2). Interestingly, but surprisingly, Gomes and colleagues showed that MasR expression and mTor activity were reduced in the hippocampus of the epileptic Ang-(1-7) treated animals. These results show that Ang-(1-7) administration could represent a new avenue for developing strategies for the management of epilepsy in clinical settings. However, future work is necessary to evaluate the levels of RAS metabolites and the activity of key enzymes in these experimental interventions to completely understand the therapeutic potential of the brain RAS manipulation in epilepsy.

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