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Review
. 2021 Feb 11;10(4):702.
doi: 10.3390/jcm10040702.

"V体育官网入口" Update on New Aspects of the Renin-Angiotensin System in Hepatic Fibrosis and Portal Hypertension: Implications for Novel Therapeutic Options

Indu G Rajapaksha  1 , Lakmie S Gunarathne  1 , Peter W Angus  2 , Chandana B Herath  1   3
Affiliations
Review

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

Indu G Rajapaksha et al. J Clin Med. .

Abstract (VSports手机版)

There is considerable experimental evidence that the renin angiotensin system (RAS) plays a central role in both hepatic fibrogenesis and portal hypertension VSports手机版. 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. .

Keywords: Mas related G protein-coupled receptor type-D; angiotensin converting enzyme 2; angiotensin-(1–7); liver fibrosis and cirrhosis; portal hypertension; renin angiotensin system. V体育安卓版.

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"V体育平台登录" Conflict of interest statement

The authors declare no conflict of interest.

Figures (VSports在线直播)

Figure 1
Figure 1
The ‘balance’ between the two arms of the renin angiotensin system (RAS). Graphical representation of the classical arm (ACE/Angiotensin II/AT1R) and the alternate arm (ACE2/Angiotensin-(1–7)/MasR) of the RAS where the alternate arm counter-balances the deleterious effects of the classical arm. Angiotensin II can exert its effects via the angiotensin II type 1 receptor (AT1R). Whilst angiotensin-(1–7) of the alternate RAS acts mainly via the Mas receptor (MasR), recent evidence suggests that it also transduces its signal via the Mas related G protein-coupled receptor type-D (MrgD). ACE: angiotensin converting enzyme; ACE2: angiotensin converting enzyme 2.
Figure 2
Figure 2
Activation of hepatic stellate cells (HSCs) by immature liver sinusoidal endothelial cells (LSECs). Reduced release of heparin-binding epidermal growth factor (HB-EGF) with concomitant increase in fibronectin isoform EIIIA release by bone marrow-derived immature LSECs activates HSCs. BM sprocs, bone marrow (BM) derived sinusoidal endothelial cell progenitor cells (sprocs). BM: bone marrow; HB-EGF: heparin-binding epidermal growth factor.
Figure 3
Figure 3
ACE2 protein expression in the liver of healthy controls and in patients with primary sclerosing cholangitis (PSC). Angiotensin converting enzyme (ACE2), the expression of which is very low in healthy livers (left panel), is upregulated in the cirrhotic livers of patients with primary sclerosing cholangitis (PSC) (right panel). Upregulated ACE2 may be important in counter-regulating the ACE and angiotensin II-driven profibrotic effects of the classical renin angiotensin system. Arrowhead, ACE2 staining; DAPI, nuclear staining; magnification, ×100.
Figure 4
Figure 4
Role of the renin angiotensin system in cirrhotic portal hypertension. Development of portal hypertension in cirrhosis is a combined effect of the changes that occur within the intrahepatic and splanchnic vascular beds. In the cirrhotic liver, vasoconstrictor peptide angiotensin II (Ang II) signals through its receptor Ang II type 1 receptor (AT1R) in activated hepatic stellate cells (HSCs) to increase the extracellular matrix proteins (ECM) deposition, creating a fixed barrier to the incoming portal blood flow which raises portal pressure. In addition, Ang II also promotes the contraction of the activated HSCs and vascular smooth muscle cells (VSMCs), further increasing intrahepatic vascular tone, exacerbating portal pressure. Increased intrahepatic resistance is further augmented by the reduced release of vasodilatory molecules such as nitric oxide (NO) from vascular/sinusoidal endothelial cells (VECs) in the cirrhotic livers. In addition, the intrahepatic vasodilatory function of angiotensin-(1–7) (Ang-(1–7)) peptide produced from Ang II by ACE2 action is also diminished, further contributing to intrahepatic resistance. In contrast, in the cirrhotic splanchnic vascular bed, circulating Ang-(1–7) increases the release of NO via its putative receptor Mas (MasR) and possibly other factors such as endothelium-derived hyperpolarizing factors (EDHFs) via the Mas related G protein-coupled receptor type-D (MrgD) from VECs. This promotes the relaxation of VSMCs which leads to dilatation of the splanchnic vascular bed leading to an increased portal blood flow. This further aggravates portal pressure. Splanchnic vasodilatation is also aggravated by intrinsic splanchnic vascular hypocontractility to vasoconstrictors such as Ang II. ACE, angiotensin converting enzyme; ACE2, angiotensin converting enzyme 2; eNOS, endothelial nitric oxide synthase. Adapted from [102].
Figure 5
Figure 5
Portal pressure responses to the blockade of the receptors of the alternate renin angiotensin system (RAS) in cirrhotic rat models induced by carbon tetrachloride (CCl4) injections or bile duct ligation (BDL), and splanchnic and hepatic vascular expression of the receptors, MasR and Mas related G protein-coupled receptor type-D (MrgD). (A) Portal pressure responses 5 min after a bolus injection of MasR blocker D-Ala7-Ang-(1–7) (A779) (10 µg/kg) or MrgD blocker D-Pro7-Ang-(1–7) (D-Pro) (10 µg/kg) in CCl4 and BDL rats. Both MasR and MrgD blockade produced a significant reduction of portal pressure likely via blocking angiotensin-(1–7)-mediated dilatation of the splanchnic vascular bed. (B) Gene expression of MasR and MrgD in cirrhotic mesenteric and hepatic vascular beds of CCl4 and BDL models compared with sham-operated or healthy control livers. In the splanchnic vasculature of cirrhotic rats, both MasR and MrgD are upregulated, suggesting that both these receptors likely play an important role in angiotensin-(1–7)-mediated splanchnic vasodilatation in cirrhosis. Although the MasR is upregulated in the cirrhotic livers, there was no change in the expression of MrgD suggesting that MasR, but not MrgD contributes to the regulation of hepatic vascular resistance in cirrhosis. Adapted from [100].
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