Up-regulation of components of the renin–angiotensin system in liver fibrosis in the rat induced by CCL4

Therapeutic interventions for liver fibrosis are still limited due to the complicated molecular pathogenesis. Renin–angiotensin system (RAS) seems to contribute to the development of hepatic fibrosis. Therefore, we aimed to examine the effect of RAS inhibition on CCl4-induced liver fibrosis. Mice were treated with silymarin (30 mg·kg−1), perindopril (1 mg·kg−1), fosinopril (2 mg·kg−1), or losartan (10 mg·kg−1). The administration of RAS inhibitors improved liver histology and decreased protein expression of alpha smooth muscle actin (α-SMA) and hepatic content of hydroxyproline. These effects found to be mediated via inactivation of nuclear transcription factor kappa B (NFκB) pathway by the inhibition of NFκB p65 phosphorylation at the Ser536 residue and phosphorylation-induced degradation of nuclear factor kappa-B inhibitor alpha (NFκBia) subsequently inhibited NFκB-induced TNF-α and TGF-β1, leading to lower levels of tissue inhibitor of metalloproteinase-1 (TIMP-1) and vascular endothelial growth factor (VEGF). We concluded that the tissue affinity of the angiotensin converting enzyme inhibitors (ACEIs) has no impact on its antifibrotic activity and that interfering the RAS either through the inhibition of ACE or the blockade of AT1R has the same therapeutic benefit. These results suggest RAS inhibitors as promising candidates for further clinical trials in the management of hepatic fibrosis.

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Targeting the renin–angiotensin system in liver fibrosis

Hepatology International ◽

10.1007/s12072-016-9740-7 ◽

2016 ◽

Vol 10 (5) ◽

pp. 730-732

Author(s):

Pau Sancho-Bru ◽

Pere Ginès

Keyword(s):

Liver Fibrosis ◽

Renin Angiotensin System ◽

Angiotensin System ◽

Renin Angiotensin

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Update on new aspects of the renin–angiotensin system in liver disease: clinical implications and new therapeutic options

Clinical Science ◽

10.1042/cs20120030 ◽

2012 ◽

Vol 123 (4) ◽

pp. 225-239 ◽

Cited By ~ 49

Author(s):

Josephine A. Grace ◽

Chandana B. Herath ◽

Kai Yan Mak ◽

Louise M. Burrell ◽

Peter W. Angus

Keyword(s):

Portal Hypertension ◽

Liver Fibrosis ◽

Portal Pressure ◽

Renin Angiotensin System ◽

Active Role ◽

Angiotensin System ◽

Renin Angiotensin ◽

Hepatic Expression ◽

Important Regulator

The RAS (renin–angiotensin system) is now recognized as an important regulator of liver fibrosis and portal pressure. Liver injury stimulates the hepatic expression of components of the RAS, such as ACE (angiotensin-converting enzyme) and the AT1 receptor [AngII (angiotensin II) type 1 receptor], which play an active role in promoting inflammation and deposition of extracellular matrix. In addition, the more recently recognized structural homologue of ACE, ACE2, is also up-regulated. ACE2 catalyses the conversion of AngII into Ang-(1–7) [angiotensin-(1–7)], and there is accumulating evidence that this ‘alternative axis’ of the RAS has anti-fibrotic, vasodilatory and anti-proliferative effects, thus counterbalancing the effects of AngII in the liver. The RAS is also emerging as an important contributor to the pathophysiology of portal hypertension in cirrhosis. Although the intrahepatic circulation in cirrhosis is hypercontractile in response to AngII, resulting in increased hepatic resistance, the splanchnic vasculature is hyporesponsive, promoting the development of the hyperdynamic circulation that characterizes portal hypertension. Both liver fibrosis and portal hypertension represent important therapeutic challenges for the clinician, and there is accumulating evidence that RAS blockade may be beneficial in these circumstances. The present review outlines new aspects of the RAS and explores its role in the pathogenesis and treatment of liver fibrosis and portal hypertension.

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