title: Therapeutic effects of the direct renin inhibitor, aliskiren, on non-alcoholic steatohepatitis in fatty liver Shionogi ob/ob male mice.
abstract: OBJECTIVE
  Non-alcoholic steatohepatitis (NASH) is a manifestation of metabolic syndrome in the liver that is characterized by hepatic fat accumulation, inflammation and varying degrees of fibrosis. The renin-angiotensin system (RAS) appears to play important roles in NASH. Direct renin inhibitors (DRI) reduce plasma renin activity (PRA) through interaction with the active site of the enzyme and reduce the formation of angiotensin-II (AT-II). Therefore, the DRI aliskiren may further suppress the RAS. This study examined the effects of aliskiren on NASH in fatty liver Shionogi (FLS)-ob/ob male mice that are the closest animal model of metabolic syndrome-related NASH in humans.
  
  
  METHODS
  Aliskiren (100 mg/kg per day, aliskiren group) or a placebo (control group) was p.o. administrated to eight FLS-ob/ob mice each for 16 weeks and factors including steatosis, fibrosis, inflammation and oxidative stress were compared between the two groups.
  
  
  RESULTS
  Amounts of hepatic fibrosis were significantly lower in the aliskiren group than in the control group. Areas of α-smooth muscle actin positivity, the numbers of F4/80 positive, 8-hydroxy-2-deoxyguanosine positive cells and immunohistochemical staining of 4-hydroxynonenal were also significantly decreased in the aliskiren group. Levels of RNA expression for transforming growth factor-β1, connective tissue growth factor and monocyte chemoattractant protein-1 were significantly lower in the aliskiren group.
  
  
  CONCLUSIONS
  Aliskiren attenuated the progression of hepatic fibrosis by inhibiting the activation of hepatic stellate and Kupffer cells and by reducing oxidative stress.
authors.affiliation: Division of Medicine and Clinical Science, Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University, Yonago, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Kishina
authors.forename: Masahiko
authors.initials: M
authors.lastname: Koda
authors.forename: Jun
authors.initials: J
authors.lastname: Kato
authors.forename: Shiho
authors.initials: S
authors.lastname: Tokunaga
authors.forename: Tomomitsu
authors.initials: T
authors.lastname: Matono
authors.forename: Takaaki
authors.initials: T
authors.lastname: Sugihara
authors.forename: Masaru
authors.initials: M
authors.lastname: Ueki
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Murawaki
keywords: direct renin inhibitors; liver fibrosis; liver steatosis; non-alcoholic steatohepatitis; oxidative stress