Angiotensin II Activates I kappa B Kinase Phosphorylation of RelA at Ser(536) to Promote Myofibroblast Survival and Liver Fibrosis

作者：Oakley Fiona; Teoh Victoria; Ching A Sue Gemma; Bataller Ramon; Colmenero Jordi; Jonsson Julie R; Eliopoulos Aristides G; Watson Martha R; Manas Derek; Mann Derek A^*

来源：Gastroenterology, 2009, 136(7): 2334-2344.

DOI：10.1053/j.gastro.2009.02.081

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.

• 出版日期2009-6