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Therapeutic effects of the direct renin inhibitor, aliskiren, on non‐alcoholic steatohepatitis in fatty liver S hionogi ob/ob male mice
Author(s) -
Kishina Manabu,
Koda Masahiko,
Kato Jun,
Tokunaga Shiho,
Matono Tomomitsu,
Sugihara Takaaki,
Ueki Masaru,
Murawaki Yoshikazu
Publication year - 2014
Publication title -
hepatology research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.123
H-Index - 75
eISSN - 1872-034X
pISSN - 1386-6346
DOI - 10.1111/hepr.12186
Subject(s) - aliskiren , steatohepatitis , medicine , endocrinology , steatosis , renin inhibitor , fibrosis , inflammation , renin–angiotensin system , fatty liver , oxidative stress , hepatic stellate cell , metabolic syndrome , angiotensin ii , hepatic fibrosis , chemistry , receptor , diabetes mellitus , blood pressure , disease
Aim 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 S hionogi ( 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. Conclusion Aliskiren attenuated the progression of hepatic fibrosis by inhibiting the activation of hepatic stellate and Kupffer cells and by reducing oxidative stress.