Toggle Main Menu Toggle Search

ePrints

Angiotensin II Activates IκB Kinase Phosphorylation of RelA at Ser536 to Promote Myofibroblast Survival and Liver Fibrosis

Lookup NU author(s): Professor Fiona Oakley, Dr Martha Watson, Professor Derek Manas, Professor Derek Mann

Downloads

Full text for this publication is not currently held within this repository. Alternative links are provided below where available.


Abstract

Background & AimS: The transcription factor nuclear factor-kappa B (NF)-kappa B promotes survival of hepatic myofibroblasts and fibrogenesis through poorly defined mechanisms. We investigated the activities of angiotensin II and I kappa B kinase (IKK) in regulation of NF-kappa B activity and the role of these proteins in liver fibrosis in rodents and humans. Methods: Phosphorylation of the NF-kappa B subunit RelA at serine 536 (P-Ser(536)-RelA) was detected by immunoblot and immunohistochemical analyses. P-Ser(536)-RelA function was assessed using vectors that expressed mutant forms of RelA, cell-permeable blocking peptides, and assays for RelA nuclear transport and apoptosis. Levels of P-Ser(536)-RelA were compared with degree of fibrosis in liver sections from chronically injured rats and patients with hepatitis C virus-mediated fibrosis who had been treated with the AT1 antagonist losartan. Results: Constitutive P-Ser(536)-RelA is a feature of human hepatic myofibroblasts, both in vitro and in situ in diseased livers. Autocrine angiotensin II stimulated IKK-mediated phosphorylation of RelA at Ser(536), which was required for nuclear transport and transcriptional activity of NF-kappa B. Inhibition of angiotensin II, the angiotensin II receptor type 1 (AT1), or IKK blocked Ser(536) phosphorylation and stimulated myofibroblast apoptosis. Treatment of fibrotic rodent liver with the angiotensin converting enzyme (ACE) inhibitor captopril or the IKK inhibitor sulphasalazine resulted in loss of P-Ser(536)-RelA-positive myofibroblasts and fibrosis regression. In human liver samples, increased numbers of P-Ser(536)-RelA-positive cells were associated with fibrosis that regressed following exposure to losartan. Conclusions: An autocrine pathway that includes angiotensin II, IKK, and P-Ser(536)-RelA regulates myofibroblast survival and can be targeted to stimulate therapeutic regression of liver fibrosis.


Publication metadata

Author(s): Oakley F, Teoh V, Ching-A-Sue G, Bataller R, Colmenero J, Jonsson JR, Eliopoulos AG, Watson MR, Manas D, Mann DA

Publication type: Article

Publication status: Published

Journal: Gastroenterology

Year: 2009

Volume: 136

Issue: 7

Pages: 2334-2344

ISSN (print): 0016-5085

ISSN (electronic): 1528-0012

Publisher: WB Saunders Co.

URL: http://dx.doi.org/10.1053/j.gastro.2009.02.081

DOI: 10.1053/j.gastro.2009.02.081


Altmetrics

Altmetrics provided by Altmetric


Actions

    Link to this publication


Share