A Combination of an Angiotensin II Receptor and a Neprilysin Inhibitor Attenuates Liver Fibrosis by Preventing Hepatic Stellate Cell Activation

• Material Type: 博士論文
• Title: A Combination of an Angiotensin II Receptor and a Neprilysin Inhibitor Attenuates Liver Fibrosis by Preventing Hepatic Stellate Cell Activation
• Author/Editor: Suzuki, Junya; Kaji, Kosuke; Nishimura, Norihisa; Kubo, Takahiro; Tomooka, Fumimasa; Shibamoto, Akihiko; Iwai, Satoshi; Tsuji, Yuki; Fujinaga, Yukihisa; Kitagawa, Koh; Namisaki, Tadashi; Akahane, Takemi; Yoshiji, Hitoshi
• Author Heading: Suzuki, Junya; Kaji, Kosuke; Nishimura, Norihisa; Kubo, Takahiro; Tomooka, Fumimasa; Shibamoto, Akihiko; Iwai, Satoshi; Tsuji, Yuki; Fujinaga, Yukihisa; Kitagawa, Koh; Namisaki, Tadashi; Akahane, Takemi; Yoshiji, Hitoshi
• Publication, Distribution, etc.: MDPI
• Publication Date: 2023-04
• Publication Date (W3CDTF): 2023-04
• Alternative Title: アンジオテンシンⅡ受容体拮抗剤とネプリライシン阻害剤の併用が肝星状細胞の活性化を抑制し，肝線維化を抑制する
• Periodical title: Biomedicines
• No. or year of volume/issue: 11 5
• Volume: 11
• Issue: 5
• Pages: 1295-
• ISSN (Periodical Title): ISSN : 2227-9059
• Degree grantor/type: 奈良県立医科大学
• Date Granted: 2024-03-14
• Dissertation Number: 甲第914号
• Degree Type: 博士（医学）
• Text Language Code: eng
• Subject Heading: liver fibrosis; hepatic stellate cell; natriuretic peptide; angiotensin II
• Target Audience: 一般
• Note (General): type:Thesis; The renin-angiotensin-aldosterone system has gained attention due to its role as a mediator of liver fibrosis and hepatic stellate cell (HSC) activation. Meanwhile, the natriuretic peptide (NP) system, including atrial NP (ANP) and C-type NP (CNP), is a counter-regulatory hormone regulated by neprilysin. Although the combination of an angiotensin receptor and a neprilysin inhibitor (sacubitril/valsartan: SAC/VAL) has shown clinical efficacy in patients with heart failure, its potential effects on hepatic fibrosis have not been clarified. This study assessed the effects of SAC/VAL in carbon tetrachloride (CCl4)-induced murine liver fibrosis as well as the in vitro phenotypes of HSCs. Treatment with SAC and VAL markedly attenuated CCl4-induced liver fibrosis while reducing α-SMA+-HSC expansion and decreasing hepatic hydroxyproline and mRNA levels of pro-fibrogenic markers. Treatment with SAC increased plasma ANP and CNP levels in CCl4-treated mice, and ANP effectively suppressed cell proliferation and TGF-β-stimulated MMP2 and TIMP2 expression in LX-2 cells by activating guanylate cyclase-A/cGMP/protein kinase G signaling. Meanwhile, CNP did not affect the pro-fibrogenic activity of LX-2 cells. Moreover, VAL directly inhibited angiotensin II (AT-II)-stimulated cell proliferation and the expression of TIMP1 and CTGF through the blockade of the AT-II type 1 receptor/protein kinase C pathway. Collectively, SAC/VAL may be a novel therapeutic treatment for liver fibrosis.; 権利情報：© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).; identifier:Biomedicines. 2023 Apr, vol.11, no.5, article no.1295; identifier:2227-9059; identifier:http://ginmu.naramed-u.ac.jp/dspace/handle/10564/4365; identifier:Biomedicines, 11(5): 1295
• Access Restrictions: インターネット公開
• Related Material (DOI): 10.3390/biomedicines11051295
• Data Provider (Database): 国立情報学研究所 : 学術機関リポジトリデータベース（IRDB）（機関リポジトリ）; https://irdb.nii.ac.jp
• Original Data Provider (Database): 奈良県立医科大学 : 奈良県立医科大学機関リポジトリ GINMU

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