Renin-Angiotensin System Modulation in Liver Diseases

The renin–angiotensin system (RAS) has emerged as a central regulator of hepatic physiology and pathology. Beyond its classical role in systemic blood pressure and volume control, local hepatic RAS components modulate inflammation, cellular metabolism, fibrogenesis and portal haemodynamics. The classical axis—comprising angiotensin-converting enzyme (ACE), angiotensin II and the AT1 receptor—promotes vasoconstriction, oxidative stress and activation of hepatic stellate cells, fostering fibrosis and elevating portal pressure. In contrast, the alternative axis—anchored by ACE2, angiotensin-(1-7) and the Mas receptor—exerts vasodilatory, anti-inflammatory and antifibrotic effects. Chronic liver injury, whether due to steatosis, viral infection or cholestasis, shifts the balance toward the profibrotic arm, contributing to cirrhosis and its complications. Therapeutic modulation of RAS in liver disease spans small-molecule inhibitors, receptor blockers and peptide agonists, aiming to rebalance opposing pathways. Preclinical models and early clinical observations support the concept that targeted RAS interventions may attenuate steatohepatitis, slow fibrosis progression and reduce portal hypertension, yet clinical translation requires optimisation of context-specific strategies and careful attention to systemic effects.

Research from Nature Portfolio

Deletion of ACE2 in murine models exacerbates hepatic steatosis, inflammation and lipogenic gene expression, whereas overexpression or pharmacological activation of the ACE2/angiotensin-(1-7)/Mas axis restores lipid-oxidative pathways and reduces oxidative stress via Akt signalling. In vitro studies confirm that angiotensin-(1-7) attenuates fatty acid accumulation and inflammatory cytokine production in hepatocyte lines, effects mediated through ATP/P2 receptor/Calmodulin and downstream Akt activation. Separately, a small-molecule activator of ACE2 originally approved for parasitic infections was shown to inhibit activation of hepatic stellate cells and Kupffer cells in biliary fibrosis models. This agent reduced NADPH oxidase assembly, reactive oxygen species generation and profibrotic transcription factors (p38, Erk1/2, Smad2/3) without altering ACE2 activity, culminating in marked attenuation of collagen deposition. Together, these findings underscore the therapeutic promise of enhancing the protective axis of RAS to counteract fibrogenic signalling in liver disease.

Renin-Angiotensin System Modulation in Liver Diseases publication trend

The graph below shows the total number of articles in renin-angiotensin system modulation in liver diseases across all publications each year (not limited to Nature Index journals).

Technical terms

Classical RAS axis: The pathway involving ACE, angiotensin II and AT1 receptor, promoting vasoconstriction and fibrosis.

Alternative RAS axis: The ACE2/angiotensin-(1-7)/Mas receptor pathway, exerting vasodilatory and antifibrotic effects.

Portal hypertension: Elevated pressure within the portal venous system, a major complication of cirrhosis.

Hepatic stellate cell: Liver pericytes that, when activated, secrete extracellular matrix leading to fibrosis.

Angiotensin-converting enzyme 2 (ACE2): A homologue of ACE that generates angiotensin-(1-7) and counterbalances classical RAS signalling.

Mineralocorticoid receptor: A nuclear receptor for aldosterone, implicated in sodium retention and fibrotic signalling.

PI3K/Akt pathway: A cell-survival and metabolic signalling cascade activated by growth factors and peptides like angiotensin-(1-7).

References

1. The Renin–Angiotensin System in Liver Disease. International Journal of Molecular Sciences (2024).
2. Angiotensin-converting enzyme 2/angiotensin-(1–7)/Mas axis activates Akt signaling to ameliorate hepatic steatosis. Scientific Reports (2016).
3. The small molecule drug diminazene aceturate inhibits liver injury and biliary fibrosis in mice. Scientific Reports (2018).
4. Eplerenone, a mineralocorticoid receptor inhibitor, reduces cirrhosis associated changes of hepatocyte glucose and lipid metabolism. Cell Communication and Signaling (2024).
5. Liraglutide Attenuates Non-Alcoholic Fatty Liver Disease in Mice by Regulating the Local Renin-Angiotensin System. Frontiers in Pharmacology (2020).