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

Theodor Bilharz Research Institute

Bibliographic Information

Authors: Saber S.; Mahmoud A.A.A.; Helal N.S.; El-Ahwany E.; Abdelghany R.H.

Journal: Canadian Journal of Physiology and Pharmacology

Publisher: Canadian Science Publishing

Publication Date: June 2018

Volume / Issue: Volume 96 / Issue 6

Pages: 569–576

ISSN: 84212

DOI: 10.1139/cjpp-2017-0728

Scopus: View on Scopus

PubMed: 29425464

Document Type: Article

Authors and Affiliations

Saber S., Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt; Mahmoud A.A.A., Department of Pharmacology, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt, Department of Pharmacology, Oman Pharmacy Institute, Ministry of Health, Muscat, Oman; Helal N.S., Department of Pathology, Theodor Bilharz Research Institute, Giza, Egypt; El-Ahwany E., Department of Immunology, Theodor Bilharz Research Institute, Giza, Egypt; Abdelghany R.H., Department of Pharmacology, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt

Abstract

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. © 2018, Canadian Science Publishing. All rights reserved.

Keywords

CCl<sub>4</sub>; Fibrosis; NFκB; NFκBia; Renin–angiotensin system; Actins; Alanine Transaminase; alpha-Fetoproteins; Animals; Carbon Tetrachloride; Gene Expression Regulation; Hydroxyproline; Liver Cirrhosis; Male; Matrix Metalloproteinase 2; Mice; NF-kappa B; Renin-Angiotensin System; Tissue Inhibitor of Metalloproteinase-1; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; alpha fetoprotein; alpha smooth muscle actin; fosinopril; gelatinase A; I kappa B kinase alpha; immunoglobulin enhancer binding protein; losartan; perindopril; silymarin; tissue inhibitor of metalloproteinase 1; transforming growth factor beta1; tumor necrosis factor; vasculotropin; actin; alanine aminotransferase; alpha-smooth muscle actin, mouse; animal experiment; animal model; animal tissue; Article; clinical assessment; controlled study; drug effect; enzyme activation; enzyme inhibition; liver fibrosis; liver histology; liver tissue; mouse; nonhuman; priority journal; protein degradation; protein expression; protein phosphorylation; renin angiotensin aldosterone system; animal; blood; chemically induced; metabolism; pathology; pathophysiology

Citation Information

Scopus Citations: 32

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