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

Abstract

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-kappaB 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.

CARMA3/Bcl10/MALT1-dependent NF-κB activation mediates angiotensin II-responsive inflammatory signaling in nonimmune cells

“…The liver is an example of a major target organ of Ang II proinflammatory action, because both hepatocytes and hepatic stellate cells express the type I Ang II receptor (AT 1 R), a member of the seven transmembranespanning G protein-coupled receptor superfamily (2)(3)(4). In several experimental models of liver injury, AT 1 -dependent Ang II signaling has been shown to be crucial for the development of hepatic fibrosis and cirrhosis, effects that are related to its induction of acute phase reactants, inflammatory and fibrogenic cytokines, and extracellular matrix proteins (5)(6)(7)(8)(9)(10)(11). These effects of Ang II appear independent of the underlying source of injury and have been documented in settings as diverse as bile-duct stenosis and CCl 4 poisoning (7,8).…”

Role of the renin-angiotensin system in hepatic ischemia reperfusion injury in rats

“…12 In liver, stellate cells have been shown to respond to AngII to produce proinflammatory and profibrotic cytokines and chemokines and reactive oxygen species. 13,14 Although the role other hepatic cells play in response to the AngII is less understood, Kupffer cells also have been shown to express the AT1 receptor under basal conditions. 15 Importantly, chronic systemic infusion of subpressor levels of AngII has been shown to cause a proinflammatory and profibrotic response in rat liver.…”

“…15 Importantly, chronic systemic infusion of subpressor levels of AngII has been shown to cause a proinflammatory and profibrotic response in rat liver. 13 However, mechanisms by which the RAS may play a role in mediating hepatic inflammation remain unclear. The purpose of the current study therefore was to determine the potential role of the RAS in inflammation and damage in acute ischemia and reperfusion injury in rat liver and to test the hypothesis that captopril and losartan exert protective effects under these conditions.…”

Angiotensin converting enzyme 2 (ACE2) activity in fetal calf serum: implications for cell culture research

“…The effects of Ang II on hepatic stellate cells (HSC) has been extensively studied (Bataller et al 2005(Bataller et al , 2003a(Bataller et al , b, 2000Wei et al 2001;Yokohama et al 2006;Zhang et al 2003), yet little information exists on the effect of Ang-(1-7) on these cells. Most studies using cell culture use culture medium supplemented with fetal calf serum (FCS) to encourage cell growth.…”