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

Kwang Yong Shim, Young Woo Eom, Moon Young Kim, Seong Hee Kang, Soon Koo Baik, Kwang Yong Shim, Young Woo Eom, Moon Young Kim, Seong Hee Kang, Soon Koo Baik

Abstract

The renin-angiotensin system (RAS) is an important regulator of cirrhosis and portal hypertension. As hepatic fibrosis progresses, levels of the RAS components angiotensin (Ang) II, Ang-(1-7), angiotensin-converting enzyme (ACE), and Ang II type 1 receptor (AT1R) are increased. The primary effector Ang II regulates vasoconstriction, sodium homoeostasis, fibrosis, cell proliferation, and inflammation in various diseases, including liver cirrhosis, through the ACE/Ang II/AT1R axis in the classical RAS. The ACE2/Ang-(1-7)/Mas receptor and ACE2/Ang-(1-9)/AT2R axes make up the alternative RAS and promote vasodilation, antigrowth, proapoptotic, and anti-inflammatory effects; thus, countering the effects of the classical RAS axis to reduce hepatic fibrogenesis and portal hypertension. Patients with portal hypertension have been treated with RAS antagonists such as ACE inhibitors, Ang receptor blockers, and aldosterone antagonists, with very promising hemodynamic results. In this review, we examine the RAS, its roles in hepatic fibrosis and portal hypertension, and current therapeutic approaches based on the use of RAS antagonists in patients with portal hypertension.

Keywords: Angiotensins; Hepatic fibrosis; Hypertension, portal; Receptors, angiotensin; Renin-angiotensin system.

Conflict of interest statement

No potential conflict of interest relevant to this article was reported.

Figures

Figure 1.
Figure 1.
Overview of the renin-angiotensin system (RAS). In the RAS pathways, angiotensin (Ang) II is the main effector regulating vasoconstriction, sodium homoeostasis, fibrosis, cell proliferation, and inflammation in various diseases, including liver cirrhosis, via the angiotensin-converting enzyme (ACE)/Ang II/Ang II type 1 receptor (AT1R) axis, which defines the classical RAS. Mediators of the alternative RAS have vasodilatory, antigrowth, proapoptotic, and anti-inflammatory properties that counterbalance the effects of the classical RAS axis to reduce hepatic fibrogenesis and portal hypertension. Ang II type 2 receptor (AT2R), Ang-(1–7) Mas receptor (MasR), ACE inhibitor (ACEi), AT1R blocker (ARB), mitogen-activated protein kinase (MAPK), Janus kinase (JAK), and signal transducer and activator of transcription (STAT), extracellular signal-regulated kinase (ERK), transforming growth factor β1 (TGF-β1), plasminogen activator inhibitor-1 (PAI-1), nitric oxide (NO), NO synthase (NOS), α-smooth muscle actin (α-SMA). NADPH, nicotinamide adenine dinucleotide phosphate.

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