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

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


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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.


DOI: 10.1053/j.gastro.2009.02.081


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