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Regul Pept. 2007 Jan 10;138(1):15-25. Epub 2006 Sep 12.

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

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Department of Emergency, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.



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-kappaB (NF-kappaB) 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-kappaB and AP-1 pathway during hepatic fibrogenesis.


To assess the effect of AECI and Angiotensin II type 1 receptor (AT-1 receptor) blocker on NF-kappaB 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 not 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-kappaB and AP-1 were analyzed by Electrophoretic mobility shift assay (EMSA). Western blot was used to detect expression of IkappaBalpha and Phospho-P42/44. RT-PCR was used to detect the expressions of tumor necrosis factor alpha (TNFalpha) mRNA and alpha1 (I) procollagen mRNA.


AECI and AT-1 receptor blocker exert anti-fibrosis effect through inhibiting NF-kappaB activation in liver. Ang II and Aldo increase HSCs NF-kappaB activity and NF-kappaB target gene-TNFalpha expression by inhibiting IkappaBalpha expression in a redox-sensitive manner. Ang II and Aldo also markedly increase HSCs AP-1 activity and AP-1 target gene-alpha1 (I) procollagen mRNA expression via ERK1/2 pathway in a redox-sensitive manner.


These results show that stimulation of NF-kappaB and AP-1 pathway mediate hepatic fibrogenesis induced by intrahepatic RAAS.

[Indexed for MEDLINE]

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