Angiotensin II activates I kappaB kinase phosphorylation of RelA at Ser 536 to promote myofibroblast survival and liver fibrosis

Gastroenterology. 2009 Jun;136(7):2334-2344.e1. doi: 10.1053/j.gastro.2009.02.081. Epub 2009 Mar 18.


Background & aims: The transcription factor nuclear factor-kappaB (NF)-kappaB promotes survival of hepatic myofibroblasts and fibrogenesis through poorly defined mechanisms. We investigated the activities of angiotensin II and I kappaB kinase (IKK) in regulation of NF-kappaB activity and the role of these proteins in liver fibrosis in rodents and humans.

Methods: Phosphorylation of the NF-kappaB 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-kappaB. 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 types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Angiotensin II / pharmacology*
  • Animals
  • Blotting, Western
  • Cell Survival / drug effects
  • Cell Survival / physiology*
  • Cells, Cultured
  • Disease Models, Animal
  • Enzyme Activation / drug effects
  • Hepatocytes / metabolism*
  • Hepatocytes / pathology
  • Humans
  • Immunohistochemistry
  • Liver Cirrhosis / metabolism
  • Liver Cirrhosis / pathology*
  • Male
  • Microscopy, Confocal
  • NF-kappa B / drug effects
  • NF-kappa B / metabolism*
  • Phosphorylation / physiology
  • Probability
  • RNA, Transfer, Ser / drug effects
  • RNA, Transfer, Ser / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sensitivity and Specificity
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Transcription Factor RelA / metabolism*


  • NF-kappa B
  • RNA, Transfer, Ser
  • Transcription Factor RelA
  • Angiotensin II