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1 Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
2 Department of Cell Biology and Anatomy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
3 Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
* To whom correspondence should be addressed. E-mail: rarippe{at}med.unc.edu.
Recent evidence indicates that angiotensin II (ANGII) plays an important role in liver fibrogenesis. However, the underlying mechanisms are largely unknown. In advanced chronic liver diseases, circulating levels of ANGII are frequently elevated. We investigated the hepatic effects of prolonged systemic infusion of ANGII in normal rats. Saline or ANGII at sub-pressor and pressor doses (15 and 50 ng/kg/h, respectively) were infused to normal rats for 4 weeks through a subcutaneous osmotic pump. Infusion of ANGII resulted in liver injury, as assessed by elevated serum liver enzymes. Livers from ANGII-perfused rats showed activation of c-Jun N-terminal kinase and extracellular-regulated kinase as well as increased NF
B and AP-1 DNA-binding activity. Moreover, ANGII perfusion induced oxidative stress, increased concentration of pro-inflammatory cytokines and up-regulated the inflammatory proteins inducible nitric oxide synthase and cyclooxygenase-2. Histological examination of the livers from ANGII-infused rats showed mild portal inflammation as well as thickening and thrombosis of small hepatic vessels. ANGII-treated livers showed accumulation of CD43 positive inflammatory cells and activated hepatic stellate cells (HSCs) at the pericentral areas. A slight increase in collagen synthesis was observed, as assessed by Sirius red staining and hepatic hydroxyproline. All these effects were observed when ANGII was perfused at sub-pressor and pressor doses. ANGII also accelerated the activation of primary cultured rat HSCs. In conclusion, increased systemic ANGII can induce liver injury by promoting pro-inflammatory events and vascular damage. ANGII-induced hepatic effects are not dependent on increase in arterial pressure.
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