Selective aldosterone blocker ameliorates the progression of non-alcoholic steatohepatitis in rats.
Although non-alcoholic steatohepatitis (NASH) may progress to cirrhosis and hepatocellular carcinoma (HCC), no effective therapeutic modalities have been fully established yet. Recent studies have shown that the renin-angiotensin-aldosterone-system plays an important role in NASH. The aim of our current study was to elucidate the effects of aldosterone (Ald) inhibition on the progression of NASH. In the choline-deficient L-amino acid-defined diet-induced rat NASH model, the effects of a clinically used selective Ald blocker (SAB) were elucidated in conjunction with the activated hepatic stellate cells (HSC) and neovascularization, which are both known to play important roles in liver fibrosis development and hepatocarcinogenesis, respectively. Liver fibrosis development and the glutathione-S-transferase placental form-positive pre-neoplastic lesions were both markedly attenuated by SAB along with the suppression of the activated HSC and neovascularization. SAB inhibited the hepatic expression of transforming growth factor-beta 1 and also that of the vascular endothelial growth factor. Our in vitro study showed that SAB also inhibited the Ald-induced HSC proliferation and in vitro angiogenesis in a dose-dependent manner. These results indicated that Ald plays a pivotal role in the progression of NASH. Considering that SAB is already widely used in clinical practice, this drug could represent a potential new strategy against NASH in the future.
Noguchi
Ryuichi
R
Third Department of Internal Medicine, Nara Medical University, Nara, Japan.
Yoshiji
Hitoshi
H
Ikenaka
Yasuhide
Y
Kaji
Kosuke
K
Shirai
Yusaku
Y
Aihara
Yosuke
Y
Yamazaki
Masaharu
M
Namisaki
Tadashi
T
Kitade
Mitsuteru
M
Yoshii
Junichi
J
Yanase
Koji
K
Kawaratani
Hideto
H
Tsujimoto
Tatsuhiro
T
Fukui
Hiroshi
H
D000450:Aldosterone / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D018450:Disease Progression; D005234:Fatty Liver / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D012084:Renin-Angiotensin System / Q000502:physiology
D000450:Aldosterone