Renin-angiotensin system in the pathogenesis of liver fibrosis

Hepatic fibrosis is considered a common response to many chronic hepatic injuries. It is a multifunctional process that involves several cell types, cytokines, chemokines and growth factors leading to a disruption of homeostatic mechanisms that maintain the liver ecosystem. In spite of many studies regarding the development of fibrosis, the understanding of the pathogenesis remains obscure. The hepatic tissue remodeling process is highly complex, resulting from the balance between collagen degradation and synthesis. Among the many mediators that take part in this process, the components of the Renin angiotensin system （RAS） have progressively assumed an important role. Angiotensin （Ang） II acts as a profibrotic mediator and Ang-（1-7）, the newly recognized RAS component, appears to exert a counter-regulatory role in liver tissue. We briefly review the liver fibrosis process and current aspects of the RAS. This review also aims to discuss some experimental evidence regarding the participation of RAS mediators in the pathogenesis of liver fibrosis, focusing on the putative role of the ACE2-Ang-（1-7）- Mas receptor axis.

Renin angiotensin system in liver diseases: Friend or foe?

In the last three decades,the understanding of the renin angiotensin system(RAS)has been changed by the discoveries of functional local systems,novel biologically active peptides,additional specific receptors,alternative pathways of angiotensin(Ang)?Ⅱ?generation,and new roles for enzymes and precursor components other than those in Ang?Ⅱ?synthesis.In this regard,the discovery that Ang-(1-7)opposes the pressor,proliferative,pro-fibrotic,and pro-inflammatory effects mediated by Ang?Ⅱ?has contributed to the realization that the RAS is composed of two axes.The first axis consists of the angiotensin-converting enzyme(ACE),with Ang?Ⅱ?as the end product,and the angiotensin type 1(AT1)receptor as the main effector mediating the biological actions of Ang?Ⅱ.The second axis results from ACE2-mediated hydrolysis of Ang?Ⅱ,leading to the production of Ang-(1-7),with the Mas receptor as the main effector conveying the vasodilatory,antiproliferative,anti-fibrotic,and anti-inflammatory effects of Ang-(1-7).Experimental and clinical studies have shown that both axes of the RAS may take part in the pathogenesis of liver diseases.In this manuscript,we summarize the current evidence regarding the role of RAS in hepatic cirrhosis and its complications,including hemodynamic changes and hepatorenal syndrome.The therapeutic potential of the modulation of RAS molecules in liver diseases is also discussed.

Therapeutic potential of targeting the renin angiotensin system in portal hypertension

Portal hypertension is responsible for the bulk of the morbidity and mortality in patients with cirrhosis.Drug therapy to reduce portal pressure involves targeting two vascular beds.The first approach is to reduce intra hepatic vascular tone induced by the activity of powerful vasocontrictors such as angiotensin Ⅱ,endothelin-1 and the sympathetic system and mediated via contraction of perisinusoidal myofibroblasts and pervascular smooth muscle cells.The second approach is to reduce mesenteric and portal blood flow.Non-selective b-blockers are widely used and have been shown to prolong patient survival and reduce oesophageal variceal bleeding in advanced cirrhosis.However many patients are unable to tolerate these drugs and they are ineffective in a significant proportion of patients.Unfortunately there are no other drug therapies that have proven efficacy in the treatment of portal hypertension and prevention of variceal bleeding.This review briefly outlines current therapeutic approaches to themanagement of portal hypertension,and the evidence supporting the role of the renin angiotensin system(RAS) and the use of RAS blockers in this condition.It will also outline recent advances in RAS research that could lead to the development of new treatments focusing in particular on the recently discovered "alternate axis" of the RAS.

Effect of propranolol on the splanchnic and peripheral renin angiotensin system in cirrhotic patients

AIM:To evaluate the effect of β-blockade on angiotensins in the splanchnic and peripheral circulation of cirrhotic patients and also to compare hemodynamic parameters during liver transplantation according to propranolol pre-treatment or not. METHODS:Patients were allocated into two groups:outpatients with advanced liver disease(LD) and during liver transplantation(LT). Both groups were subdivided according to treatment with propranolol or not. Plasma was collected through peripheral venipuncture to determine plasma renin activity(PRA),Angiotensin(Ang) Ⅰ,Ang Ⅱ,and Ang-(1-7) levels by radioimmunoassay in LD group. During liver transplantation,hemodynamic parameters were determined and blood samples were obtained from the portal vein to measure renin angiotensin system(RAS) components.RESULTS:PRA,Ang Ⅰ,Ang Ⅱ and Ang-(1-7) were signifi cantly lower in the portal vein and periphery in all subgroups treated with propranolol as compared to non-treated. The relationships between Ang-(1-7) and Ang Ⅰ levels and between Ang Ⅱ and Ang Ⅰ were significantly increased in LD group receiving propranolol. The ratio between Ang-(1-7) and Ang Ⅱ remained unchanged in splanchnic and peripheral circulation in patients under β-blockade,whereas the relationship between Ang Ⅱ and Ang Ⅰ was significantly increased in splanchnic circulation of LT patients treated with propranolol. During liver transplantation,cardiac output and index as well systemic vascular resistance and index were reduced in propranolol-treated subgroup. CONCLUSION:In LD group,propranolol treatment reduced RAS mediators,but did not change the ratio between Ang-(1-7) and Ang Ⅱ in splanchnic and peripheral circulation. Furthermore,the modification of hemodynamic parameters in propranolol treated patients was not associated with changes in the angiotensin ratio.

Comparison between laparoscopic surgery and laparotomy for the treatment of acute ruptured ectopic pregnancy

Objective: To study the stress reaction after laparoscopic surgery and laparotomy for the treatment of acute ruptured ectopic pregnancy. Methods: 68 patients with acute ruptured ectopic pregnancy who received emergency surgical treatment in Pangang Group General Hospital between July 2013 and September 2016 were selected and analyzed retrospectively, including 29 patients with laparoscopic surgery and 39 patients with laparotomy who were included in the laparoscopy group and laparotomy group respectively. Before operation as well as 1d and 3d after operation, serum was collected to detect biochemical indexes and stress hormones. Results: 1d and 3d after operation, serum Alb, AST, ALT, BUN, Scr and UA levels were not significantly different between laparoscopy group and laparotomy group (P>0.05);serum NE (149.65±17.58 vs. 186.61±23.52, 162.32±20.15 vs. 295.86±28.97 pg/ml), E (135.28±19.85 vs. 179.55±22.52, 152.11±18.52 vs. 231.38±29.58 pg/ml), ACTH (3.88±0.49 vs. 5.12±0.82, 4.39±0.52 vs. 6.58±0.92 pmol/L), Cor (177.64±20.12 vs. 224.59±35.55, 185.21±22.12 vs. 289.45±41.28 ng/ml), Ins (12.21±1.86 vs. 17.58±2.52, 18.95±2.68 vs. 27.61±4.12 IU/mL), PRA (1.65±0.25 vs. 2.18±0.35, 1.73±0.21 vs. 2.55±0.47ng/ml), AngⅡ (44.12±7.64 vs. 59.63±7.92, 52.27±7.95 vs. 76.12±9.35 pg/ml) and ALD (155.22±19.76 vs. 205.62±24.52, 189.10±22.58 vs. 316.85±42.85 pg/ml) levels of laparoscopy group were significantly lower than those of laparotomy group (P<0.05). Conclusions: Laparoscopic surgery for acute ruptured ectopic pregnancy causes less adrenal stress reaction and RAAS system stress reaction, and the overall level of trauma is lower than that of laparotomy.

Serum levels of angiotensin converting enzyme as a biomarker of liver fibrosis

The renin angiotensin system(RAS) is classically conceived as a circulating hormonal system involved in blood pressure control and hydroelectrolyte balance. The discovery that RAS components are locally expressed in a wide range of organs and tissues,including the liver,pointed to a role for this system in the pathogenesis of several conditions including hepatic fibrosis and cirrhosis. It has been widely reported that the classical RAS axis composed by the angiotensin converting enzyme(ACE)-angiotensin(Ang) Ⅱ-Ang type 1(AT1) receptor mediates pro-inflammatory,pro-thrombotic,and pro-fibrotic processes. On the other hand,the alternative axis comprising ACE2-Ang-(1-7)-Mas receptor seems to play a protective role by frequently opposing Ang Ⅱ action. Chronic hepatitis B(CHB) is one of the leading causes of liver fibrosis,accounting for the death of nearly one million people worldwide. Liver fibrosis is a key factor to determine therapeutic interventions for patients with CHB. However,the establishment of non-invasive and accurate methods to detect reversible stages of liver fibrosis is still a challenge. In an elegant study published in the 36 th issue of the World Journal of Gastroenterology,Noguchi et al showed the predictive value of serum ACE levels in detecting not only advanced stages of liver fibrosis but also initial and intermediate fibrotic stages. The serum levels of ACE might represent an accurate,non-invasive,widely available,and easy method to evaluate fibrosis related to CHB. Moreover,therapies involving the inhibition of the classical RAS axis components might be promising in the control of CHB-related liver fibrosis.