Renin–angiotensin system inhibition ameliorates CCl4-induced liver fibrosis in mice through the inactivation of nuclear transcription factor kappa B

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 CCl 4 -induced liver fibrosis. Mice...

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Bibliographic Details
Published in:Canadian journal of physiology and pharmacology 2018, Vol.96 (6), p.569-576
Main Authors: Saber, Sameh, Mahmoud, Amr A.A, Helal, Noha S, El-Ahwany, Eman, Abdelghany, Rasha H
Format: Article
Language:English
Subjects:
Actin
Angiotensin
Carbon tetrachloride
CCl
Clinical trials
Enzyme inhibitors
Enzymes
fibrose
Fibrosis
Histology
Hydroxyproline
Inactivation
Inhibition
Kinases
Liver
Metalloproteinase
Muscles
NF-κB protein
NFκB
NFκBia
Pathogenesis
Peptidyl-dipeptidase A
Pharmacology
Phosphorylation
Physiology
Renin
renin–angiotensin system
Silymarin
Smooth muscle
système rénine–angiotensine
Therapeutic applications
Tissue inhibitor of metalloproteinase 1
Transcription factors
Transforming growth factor-b1
Tumor necrosis factor-α
Vascular endothelial growth factor
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Summary: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 CCl 4 -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.
ISSN:0008-4212
1205-7541
DOI:10.1139/cjpp-2017-0728