Chronic liver injury in rats and humans upregulates the novel enzyme angiotensin converting enzyme 2

Abstract

Background: Angiotensin converting enzyme (ACE) 2 is a recently identified homologue of ACE that may counterregulate the actions of angiotensin (Ang) II by facilitating its breakdown to Ang 1-7. The reninangiotensin system (RAS) has been implicated in the pathogenesis of cirrhosis but the role of ACE2 in liver disease is not known. Aims: This study examined the effects of liver injury on ACE2 expression and activity in experimental hepatic fibrosis and human cirrhosis, and the effects of Ang 1-7 on vascular tone in cirrhotic rat aorta. Methods: In sham operated and bile duct ligated (BDL) rats, quantitative reverse transcriptase-polymerase chain reaction was used to assess hepatic ACE2 mRNA, and western blotting and immunohistochemistry to quantify and localise ACE2 protein. ACE2 activity was quantified by quenched fluorescent substrate assay. Similar studies were performed in normal human liver and in hepatitis C cirrhosis. Results: ACE2 mRNA was detectable at low levels in rat liver and increased following BDL (363-fold; p,0.01). ACE2 protein increased after BDL (23.5-fold; p,0.05) as did ACE2 activity (fourfold; p,0.05). In human cirrhotic liver, gene (.30-fold), protein expression (97-fold), and activity of ACE2 (2.4 fold) were increased compared with controls (all p,0.01). In healthy livers, ACE2 was confined to endothelial cells, occasional bile ducts, and perivenular hepatocytes but in both BDL and human cirrhosis there was widespread parenchymal expression of ACE2 protein. Exposure of cultured human hepatocytes to hypoxia led to increased ACE2 expression. In preconstricted rat aorta, Ang 1-7 alone did not affect vascular tone but it significantly enhanced acetylcholine mediated vasodilatation in cirrhotic vessels. Conclusions: ACE2 expression is significantly increased in liver injury in both humans and rat, possibly in response to increasing hepatocellular hypoxia, and may modulate RAS activity in cirrhosis.

Telmisartan attenuates hepatic fibrosis in bile duct-ligated rats

“…There is considerable animal model data supporting an antifibrotic role for the ACE2/Ang (1-7)-MAS axis of the RAS in hepatic fibrosis [1][2][3][6][7][8] . Therefore, we speculate that the RAS may be shifted away from profibrotic responses towards antifibrotic responses by the upregulation of a novel ACE2/Ang (1-7)-MAS axis in the liver.…”

“…We presume that ACE2 amplification stimulates Ang II degradation and that a decrease in ACE lessens the formation of Ang II. Moreover, Ang (1-7) could be converted to the inactive peptide fragment Ang (1)(2)(3)(4)(5) by the degradation of ACE, and ARBs are known to promote Ang (1-7) expression levels [26] . Furthermore, a decrease of ACE expression levels could offer additional protective effects for hepatic fibrosis through the increased expression of MAS levels.…”

“…Despite significant efforts, there is still no effective therapy for hepatic fibrosis. The renin-angiotensin system (RAS) plays an important role in controlling liver fibrosis [1][2][3] . It is well known that the RAS influences cell differentiation, nutrition, and fibrosis, and it has been reported to play a role in heart and kidney disease [4,5] .…”

Relationship between angiotensin-(1-7) and angiotensin II correlates with hemodynamic changes in human liver cirrhosis

“…Paizis et al [14] demonstrated that in both BDL rat and human livers there was an increased ACE2 expression and activity that might facilitate the conversion of Ang Ⅱ to Ang-(1-7). Pereira et al [12] demonstrated that the progression of liver dysfunction in BDL rats was characterized by marked changes in Ang-(1-7) and Ang Ⅱ levels and the overall activation of circulating RAS was associated with the progression of hepatic fibrosis.…”

“…While the ACE-Ang Ⅱ-AT1 receptor arm contributes to liver tissue injury and fibrosis [6] and the maintenance of basal vascular tonus in non-compensated cirrhosis [11] , the activation of the ACE2-Ang-(1-7)-Mas arm exerts antifibrotic actions [6,12,13] . In addition, it has been speculated that this counter-regulatory arm also has a role in the arterial vasodilation in liver cirrhosis [14] . In this regard, we have recently shown that chronic treatment with propranolol in cirrhotic patients was characterized by marked changes in the precursors of the RAS cascade (renin and Ang Ⅰ), with repercussions on the 2 main RAS components, Ang Ⅱ and Ang-(1-7), in the splanchnic and peripheral circulations [15] .…”