Liver fibrosis: a balance of ACEs?
There is an increasing body of evidence to suggest that the RAS (renin-angiotensin system) contributes to tissue injury and fibrosis in chronic liver disease. A number of studies have shown that components of a local hepatic RAS are up-regulated in fibrotic livers of humans and in experimental animal models. Angiotensin II, the main physiological effector molecule of this system, mediates liver fibrosis by stimulating fibroblast proliferation (myofibroblast and hepatic stellate cells), infiltration of inflammatory cells, and the release of inflammatory cytokines and growth factors such as TGF (transforming growth factor)-beta1, IL (interleukin)-1beta, MCP (monocyte chemoattractant protein)-1 and connective tissue growth factor. Furthermore, blockade of the RAS by ACE (angiotensin-converting enzyme) inhibitors and angiotensin type 1 receptor antagonists significantly attenuate liver fibrosis in experimental models of chronic liver injury. In 2000 ACE2 (angiotensin-converting enzyme 2), a human homologue of ACE, was identified. ACE2 efficiently degrades angiotensin II to angiotensin-(1-7), a peptide which has recently been shown to have both vasodilatory and tissue protective effects. This suggests that ACE2 and its products may be part of an alternate enzymatic pathway in the RAS, which counterbalances the generation and actions of angiotensin II, the ACE2-angiotensin-(1-7)-Mas axis. This review focuses on the potential roles of the RAS, angiotensin II and ACE2 in chronic liver injury and fibrogenesis.
Warner
Fiona J
FJ
A. W. Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Camperdown, NSW, Australia. f.warner@centenary.usyd.edu.au
Lubel
John S
JS
McCaughan
Geoffrey W
GW
Angus
Peter W
PW
D000804:Angiotensin II / Q000502:physiology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000818:Animals; D006801:Humans; D008103:Liver Cirrhosis / Q000188:drug therapy / Q000201:enzymology* / Q000209:etiology / Q000503:physiopathology; D007703:Peptidyl-Dipeptidase A / Q000502:physiology*; D012084:Renin-Angiotensin System / Q000502:physiology
D000806:Angiotensin-Converting Enzyme Inhibitors; D000804:Angiotensin II; D007703:Peptidyl-Dipeptidase A