Direct renin inhibitor attenuated the liver fibrosis development via suppression of angiotensin-II-mediated several biological activities

Although non-alcoholic steatohepatitis (NASH) is known to be a progressive liver disease, no widely accepted therapeutic modalities have been established in the clinical practice yet. We previously reported that the renin-angiotensin system (RAS) plays a pivotal role in NASH, and clinically used several RAS inhibitory agents suppressed the progression of NASH via inhibition of the activated hepatic stellate cell (Ac-HSC) and angiogenesis. The aim of our current study was to elucidate the effect of a clinically available direct renin inhibitor (DRI), Aliskiren, on the liver fibrogenesis in NASH. NASH model was induced by the choline-deficient L-amino acid-defined diet for 12 weeks. The effects of DRI at clinically comparable low doses on several indices were examined, especially in conjunction with Ac-HSC and neovascularization. The liver fibrosis development was markedly attenuated by DRI in parallel with the suppression of TGF-β, pro-collagen-I mRNA expression, and the Ac-HSC in a dose-dependent manner. We also observed that DRI suppressed hepatic neovascularization VEGF, and angiotensin-II production in the liver. Since DRI is widely used in the clinical practice without serious side effects, DRI could represent a potential new strategy against NASH fibrosis development in the future.