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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\u2010sensing 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\u2010converting 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\u2010derived natriuretic and vasodilating peptides (Ang1\u20109, Ang1\u20107, Ang3\u20108) and their receptors have been described. Receptor agonists or antagonists are available to affect portal hypertension and sodium retention in cirrhosis. ACE2\u2010dependent generation of Ang1\u20107 may inhibit experimental liver fibrosis. inhibition of Ang1\u20107 clearance by means of neprilysin blockade has portal hypotensive and natriuretic effects. Ang1\u201012, 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<jats:sub>1<\/jats:sub>R and AT<jats:sub>2<\/jats:sub>R receptors, their ratio being prone to pharmacological modulation.<\/jats:p>","DOI":"10.1111\/liv.14272","type":"journal-article","created":{"date-parts":[[2019,10,3]],"date-time":"2019-10-03T14:14:41Z","timestamp":1570112081000},"page":"18-31","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":57,"title":["Pathways of hepatic and renal damage through non\u2010classical activation of the renin\u2010angiotensin system in chronic liver disease"],"prefix":"10.1111","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2328-1768","authenticated-orcid":false,"given":"Giovanni","family":"Sanso\u00e8","sequence":"first","affiliation":[{"name":"Division of Gastroenterology Humanitas Gradenigo Hospital Torino 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