Pathways of hepatic and renal damage through non‐classical activation of the renin‐angiotensin system in chronic liver disease
Open accessAbstract
In liver cirrhosis, renin‐angiotensin system (RAS) activation sustains renal sodium retention and hepatic fibrogenesis. New information has recently enlivened the traditional concept of RAS. For instance, renin and prorenin bind their ubiquitous receptors, resulting in the local production of angiotensin (Ang) II; increased serum calcium and calcimimetic agents, through stimulation of extracellular calcium‐sensing receptors (CaSR), blunt renin production and lead to natriuretic effects in human and experimental cirrhosis. Alongside systemic production, there is Ang II tissue production within various organs through RAS enzymes different from angiotensin‐converting enzyme (ACE), that is chymase, tissue plasminogen activator and several cathepsins. In experimental cirrhosis, inhibition of chymase leads to natriuretic and hepatic antifibrotic effects, without changes in systemic haemodynamics. In the kidney, local RAS coordinates proximal and distal tubular sodium reabsorption. However, renalase, whose plasma and tissue levels are severely altered in experimental cirrhosis, degrades systemic and renal tubule catecholamines, antagonizing the effects of renal RAS. Angiotensinogen‐derived natriuretic and vasodilating peptides (Ang1‐9, Ang1‐7, Ang3‐8) and their receptors have been described. Receptor agonists or antagonists are available to affect portal hypertension and sodium retention in cirrhosis. ACE2‐dependent generation of Ang1‐7 may inhibit experimental liver fibrosis. inhibition of Ang1‐7 clearance by means of neprilysin blockade has portal hypotensive and natriuretic effects. Ang1‐12, whose production renin does not regulate, is converted to several different angiotensin peptides via chymase. Finally, Ang II behaves as either an antinatriuretic or a natriuretic agent, based on the tissue content of AT 1 R and AT 2 R receptors, their ratio being prone to pharmacological modulation.
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Relatively independent RAS exists in almost all organs and tissues and can play a local role through paracrine/autocrine.
“Later, it was gradually discovered that relatively independent RAS in almost all organs and tissues can play a local role in many organs and tissues through paracrine/autocrine [15–21].”
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- Authors
- Sansoè, G., Aragno, M., & Wong, F.
- Affiliations
- Division of Gastroenterology Humanitas Gradenigo Hospital Torino Italy
- University of Turin (IT)
- University of Toronto (CA)
- Venue
- Liver International
- Publisher
- Wiley
- Published
- 2019-11-04
- Volume
- 40
- Issue
- 1
- Pages
- 18-31
- ISSN
- 0106-9543 (ISSN-L)
- 1478-3223
- 1478-3231
- OpenAlex
- W2978207589
- Cited by
- 61
- References
- 128
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 9 · 2023: 13 · 2022: 9 · 2021: 14 · 2020: 5
- FWCI
- 1.27
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Liver International (publishedVersion)
- PubMed (publishedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
- Health Sciences › Medicine › Hepatology › Liver Disease and Transplantation
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- renin-angiotensin system, liver cirrhosis, chronic liver disease, renal sodium retention, liver fibrosis, chymase, angiotensin II, angiotensin-(1-7), angiotensin-(1-9), renalase, calcium-sensing receptor, neprilysin, angiotensin-converting enzyme 2, angiotensin II type 1 receptor, angiotensin II type 2 receptor, portal hypertension, sodium excretion
- MeSH terms
- Angiotensin II, Angiotensin-Converting Enzyme Inhibitors, Animals, Chronic Disease, Humans, Kidney Tubules, Proximal, Liver Diseases, Renin-Angiotensin System, Sodium
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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What counts as a claim ›How we measure confidence ›How we check this ›
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