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Volume 11
Issue 5
10.3390/biomedicines11051295
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Article

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

by
Junya Suzuki
,
Kosuke Kaji
*,
Norihisa Nishimura
,
Takahiro Kubo
,
Fumimasa Tomooka
,
Akihiko Shibamoto
,
Satoshi Iwai
,
Yuki Tsuji
,
Yukihisa Fujinaga
,
Koh Kitagawa
,
Tadashi Namisaki
,
Takemi Akahane
and
Hitoshi Yoshiji
Department of Gastroenterology, Nara Medical University, Kashihara 634-8521, Nara, Japan
*
Author to whom correspondence should be addressed.
Biomedicines 2023, 11(5), 1295; https://doi.org/10.3390/biomedicines11051295
Submission received: 14 March 2023 / Revised: 12 April 2023 / Accepted: 26 April 2023 / Published: 27 April 2023
(This article belongs to the Special Issue Liver Fibrosis: Molecular Mechanisms, Potential Therapeutic Targets and Clinical Biomarkers)
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Abstract

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.
Keywords: liver fibrosis; hepatic stellate cell; natriuretic peptide; angiotensin II liver fibrosis; hepatic stellate cell; natriuretic peptide; angiotensin II

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MDPI and ACS Style

Suzuki, J.; Kaji, K.; Nishimura, N.; Kubo, T.; Tomooka, F.; Shibamoto, A.; Iwai, S.; Tsuji, Y.; Fujinaga, Y.; Kitagawa, K.; et al. A Combination of an Angiotensin II Receptor and a Neprilysin Inhibitor Attenuates Liver Fibrosis by Preventing Hepatic Stellate Cell Activation. Biomedicines 2023, 11, 1295. https://doi.org/10.3390/biomedicines11051295

AMA Style

Suzuki J, Kaji K, Nishimura N, Kubo T, Tomooka F, Shibamoto A, Iwai S, Tsuji Y, Fujinaga Y, Kitagawa K, et al. A Combination of an Angiotensin II Receptor and a Neprilysin Inhibitor Attenuates Liver Fibrosis by Preventing Hepatic Stellate Cell Activation. Biomedicines. 2023; 11(5):1295. https://doi.org/10.3390/biomedicines11051295

Chicago/Turabian Style

Suzuki, Junya, Kosuke Kaji, Norihisa Nishimura, Takahiro Kubo, Fumimasa Tomooka, Akihiko Shibamoto, Satoshi Iwai, Yuki Tsuji, Yukihisa Fujinaga, Koh Kitagawa, and et al. 2023. "A Combination of an Angiotensin II Receptor and a Neprilysin Inhibitor Attenuates Liver Fibrosis by Preventing Hepatic Stellate Cell Activation" Biomedicines 11, no. 5: 1295. https://doi.org/10.3390/biomedicines11051295

APA Style

Suzuki, J., Kaji, K., Nishimura, N., Kubo, T., Tomooka, F., Shibamoto, A., Iwai, S., Tsuji, Y., Fujinaga, Y., Kitagawa, K., Namisaki, T., Akahane, T., & Yoshiji, H. (2023). A Combination of an Angiotensin II Receptor and a Neprilysin Inhibitor Attenuates Liver Fibrosis by Preventing Hepatic Stellate Cell Activation. Biomedicines, 11(5), 1295. https://doi.org/10.3390/biomedicines11051295

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