Angiotensin II and Aldosterone stimulating NF-κB and AP-1 activation in hepatic fibrosis of rat

Background/aims: Intrahepatic renin-angiotensin-aldosterone system (RAAS) plays a key role in the fibrogenesis of liver. However, the signal transduction mechanism underlying effects of Angiotensin II (Ang II) and Aldosterone (Aldo) on Nuclear Factor-kappa B (NF-kappa B) and active protein-1 (AP-1) pathway in hepatic fibrogenesis remains to be fully elucidated. The present study aims to investigate the signal transduction mechanism underlying effects of Ang II and Aldo on NF-kappa B and AP-1 pathway during hepatic fibrogenesis. Methods: To assess the effect of AECI and Angiotensin II type I receptor (AT-1 receptor) blocker on NF-kappa B activity in liver, a model of fibrosis was performed in rat. In vitro, hepatic stellate cells (HSCs)-T6 cells were preincubated for 1 h or riot with U0126, a specific inhibitor of extracellular signal regulated kinase (ERK), irbesartan, and N-acetylcysteine prior to exposure to Ang II or Aldo for the indicated times. DNA binding activity of NF-kappa B and AP-1 were analyzed by Electrophoretic mobility shift assay (EMSA). Western blot was used to detect expression of I kappa B alpha and Phospho-P42/44. RT-PCR was used to detect the expressions of tumor necrosis factor alpha (TNF alpha) mRNA and alpha 1 (I) procollagen mRNA. Results: AECI and AT-1 receptor blocker exert anti-fibrosis effect through inhibiting NF-kappa B activation in liver. Ang II and Aldo increase HSCs NF-kappa B activity and NF-kappa B target gene-TNF alpha expression by inhibiting I kappa B alpha expression in a redox-sensitive manner. Ang II and Aldo also markedly increase HSCs AP-1 activity and AP-1 target gene-alpha 1 (I) procollagen mRNA expression via ERK 1/2 pathway in a redox-sensitive manner. Conclusions: These results show that stimulation of NF-kappa B and AP-1 pathway mediate hepatic fibrogenesis induced by intrahepatic RAAS. (c) 2006 Elsevier B.V. All rights reserved.