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Am J Physiol Gastrointest Liver Physiol 285: G642-G651, 2003. First published May 28, 2003; doi:10.1152/ajpgi.00037.2003
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INFLAMMATION/IMMUNITY/MEDIATORS

Prolonged infusion of angiotensin II into normal rats induces stellate cell activation and proinflammatory events in liver

Ramón Bataller,1 Erwin Gäbele,1 Robert Schoonhoven,1 Terry Morris,1 Mark Lehnert,3 Liu Yang,1 David A. Brenner,1,2 and Richard A. Rippe1

1Departments of Medicine, 2Biochemistry and Biophysics, and 3Cell Biology and Anatomy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7032

Submitted 22 January 2003 ; accepted in final form 21 May 2003

Recent evidence indicates that angiotensin II (ANG II) plays an important role in liver fibrogenesis. However, the underlying mechanisms are largely unknown. In advanced chronic liver diseases, circulating levels of ANG II are frequently elevated. We investigated the hepatic effects of prolonged systemic infusion of ANG II in normal rats. Saline or ANG II at subpressor and pressor doses (15 and 50 ng·kg-1·min-1, respectively) were infused to normal rats for 4 wk through a subcutaneous osmotic pump. Infusion of ANG II resulted in liver injury, as assessed by elevated serum liver enzymes. Livers from ANG II-perfused rats showed activation of JNK and ERK as well as increased NF-{kappa}B and activating protein-1 DNA-binding activity. Moreover, ANG II perfusion induced oxidative stress, increased concentration of proinflammatory cytokines, and upregulated the inflammatory proteins inducible nitric oxide synthase and cyclooxygenase-2. Histological examination of the livers from ANG II-infused rats showed mild portal inflammation as well as thickening and thrombosis of small hepatic vessels. ANG II-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 of these effects were observed when ANG II was perfused at subpressor and pressor doses. ANG II also accelerated the activation of primary cultured rat HSCs. In conclusion, increased systemic ANG II can induce liver injury by promoting proinflammatory events and vascular damage. ANG II-induced hepatic effects are not dependent on increase in arterial pressure.

hepatic inflammation; renin-angiotensin system; cytokines


Address for reprint requests and other correspondence: R. A. Rippe, CB# 7032, Dept. of Medicine, The Univ. of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7032 (E-mail: rarippe{at}med.unc.edu).




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