The Angiotensin-converting Enzyme Inhibitor, Captopril, Suppressed Hepatic Stellate Cell Activation Via NF-kappaB or Wnt3α/β-catenin Pathway

Overview

Journal Bioengineered

Date 2021 Oct 5

PMID 34607529

Citations 4

Authors

Zhaodi Gu

Linjun Fang

Peijun Ma

Affiliations

Soon will be listed here.

Abstract

Activation of hepatic stellate cells (HSC) is associated with hepatic fibrogenesis, which is one of complications of diabetes mellitus. Captopril possesses potent anti-inflammation, oxidative stress and fibrosis effects. However, the specific molecular mechanism of captopril in high glucose (HG)-induced hepatic stellate cells has not been elucidated. Following the treatment of HG or captopril treatment for rat hepatic stellate cells (HSC-T6), cell activities were detected by Cell Counting Kit-8 (CCK8) assay. Reactive oxygen species (ROS) levels were determined by ROS staining. The expression of inflammation-related proteins (Interleukin (IL)-1β, IL-6 and IL-8) and fibrosis-related proteins (fibronectin (FN), collagen I, collagen III, collagen IV, matrix metallopeptidase (MMP-2 and MMP-9) were determined by Western blot. Captopril significantly decreased HSC-T6 cell viability induced by HG in a dose-dependent manner, as well as decreased levels of malondialdehyde (MDA), ROS, pro-inflammatory markers and fibrosis-related proteins, while upregulated superoxide dismutase (SOD) activities. We further found that captopril decreased the ratio of p-IκBα/IκBα and the ratio of p-p65/p65. Intriguing, phorbol myristate acetate (PMA) or LiCl was able to significantly reverse the captopril-induced alteration of oxidative stress-, inflammation- and fibrosis-marker levels. In conclusion, in HG-stimulated HSC-T6 cells, captopril displayed a potent ability to inhibit oxidative stress, inflammation and hepatic fibrogenesis via NF-kappaB or wnt3α/β-catenin. These results demonstrated the mechanism of captopril as well as the role of the NF-kappaB or wnt3α/β-catenin on HSC-T6 activation induced by HG.

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References

Xie Y, Song T, Huo M, Zhang Y, Zhang Y, Ma Z . Fasudil alleviates hepatic fibrosis in type 1 diabetic rats: involvement of the inflammation and RhoA/ROCK pathway. Eur Rev Med Pharmacol Sci. 2018; 22(17):5665-5677. DOI: 10.26355/eurrev_201809_15834. View

Wang Y, Sun Y, Zuo L, Wang Y, Huang Y . ASIC1a promotes high glucose and PDGF-induced hepatic stellate cell activation by inducing autophagy through CaMKKβ/ERK signaling pathway. Toxicol Lett. 2018; 300:1-9. DOI: 10.1016/j.toxlet.2018.10.003. View

Li W, Shen X, Wang Y, Zhang J . The effect of Shengpuhuang-tang on retinal inflammation in streptozotocin-induced diabetic rats by NF-κB pathway. J Ethnopharmacol. 2019; 247:112275. DOI: 10.1016/j.jep.2019.112275. View

Munsterman I, Kendall T, Khelil N, Popa M, Lomme R, Drenth J . Extracellular matrix components indicate remodelling activity in different fibrosis stages of human non-alcoholic fatty liver disease. Histopathology. 2018; 73(4):612-621. DOI: 10.1111/his.13665. View

Sakai M, Sumiyoshi T, Aoyama T, Urayama K, Yoshimura R . GPR91 antagonist and TGF-β inhibitor suppressed collagen production of high glucose and succinate induced HSC activation. Biochem Biophys Res Commun. 2020; 530(2):362-366. DOI: 10.1016/j.bbrc.2020.07.141. View

Li Z, Zhang X, Wang D, Xu J, Kou K, Wang Z . Overexpressed lncRNA GATA6-AS1 Inhibits LNM and EMT via FZD4 through the Wnt/β-Catenin Signaling Pathway in GC. Mol Ther Nucleic Acids. 2020; 19:827-840. PMC: 6976905. DOI: 10.1016/j.omtn.2019.09.034. View

Li Z, Li P, Lu Y, Sun D, Zhang X, Xu Y . A non-autonomous role of MKL1 in the activation of hepatic stellate cells. Biochim Biophys Acta Gene Regul Mech. 2019; 1862(6):609-618. DOI: 10.1016/j.bbagrm.2019.03.001. View

Liu Y, Wei M, Liu G, Song C, Yang M, Cao Z . Silencing Protease-Activated Receptor-2 alleviates ox-LDL-induced lipid accumulation, inflammation and apoptosis via activation of Wnt/β-catenin signaling. Gen Physiol Biophys. 2020; 39(5):437-448. DOI: 10.4149/gpb_2020014. View

Hu R, Wang M, Ni S, Wang M, Liu L, You H . Salidroside ameliorates endothelial inflammation and oxidative stress by regulating the AMPK/NF-κB/NLRP3 signaling pathway in AGEs-induced HUVECs. Eur J Pharmacol. 2019; 867:172797. DOI: 10.1016/j.ejphar.2019.172797. View

10.

Ebadi Z, Moradi N, Kazemi Fard T, Balochnejadmojarrad T, Chamani E, Fadaei R . Captopril and Spironolactone Can Attenuate Diabetic Nephropathy in Wistar Rats by Targeting microRNA-192 and microRNA-29a/b/c. DNA Cell Biol. 2019; 38(10):1134-1142. DOI: 10.1089/dna.2019.4732. View

11.

Boskabadi J, Askari V, Hosseini M, Boskabady M . Immunomodulatory properties of captopril, an ACE inhibitor, on LPS-induced lung inflammation and fibrosis as well as oxidative stress. Inflammopharmacology. 2018; 27(3):639-647. DOI: 10.1007/s10787-018-0535-4. View

12.

Muriach M, Flores-Bellver M, Romero F, Barcia J . Diabetes and the brain: oxidative stress, inflammation, and autophagy. Oxid Med Cell Longev. 2014; 2014:102158. PMC: 4158559. DOI: 10.1155/2014/102158. View

13.

Zhang C, Liu X, Sun H, Meng X, Bao Y, Zhang H . Octreotide attenuates hepatic fibrosis and hepatic stellate cells proliferation and activation by inhibiting Wnt/β-catenin signaling pathway, c-Myc and cyclin D1. Int Immunopharmacol. 2018; 63:183-190. DOI: 10.1016/j.intimp.2018.08.005. View

14.

Guo X, Chen Y, Hong T, Chen X, Duan Y, Li C . Induced pluripotent stem cell-derived conditional medium promotes Leydig cell anti-apoptosis and proliferation via autophagy and Wnt/β-catenin pathway. J Cell Mol Med. 2018; 22(7):3614-3626. PMC: 6010900. DOI: 10.1111/jcmm.13641. View

15.

Friedman S . Mechanisms of hepatic fibrogenesis. Gastroenterology. 2008; 134(6):1655-69. PMC: 2888539. DOI: 10.1053/j.gastro.2008.03.003. View

16.

Fujii H, Kawada N, Japan Study Group Of Nafld Jsg-Nafld . The Role of Insulin Resistance and Diabetes in Nonalcoholic Fatty Liver Disease. Int J Mol Sci. 2020; 21(11). PMC: 7312931. DOI: 10.3390/ijms21113863. View

17.

Kelleni M, Ibrahim S, Abdelrahman A . Effect of captopril and telmisartan on methotrexate-induced hepatotoxicity in rats: impact of oxidative stress, inflammation and apoptosis. Toxicol Mech Methods. 2016; 26(5):371-7. DOI: 10.1080/15376516.2016.1191576. View

18.

Zhang S, Xu L, Liang R, Yang C, Wang P . Baicalin suppresses renal fibrosis through microRNA-124/TLR4/NF-κB axis in streptozotocin-induced diabetic nephropathy mice and high glucose-treated human proximal tubule epithelial cells. J Physiol Biochem. 2020; 76(3):407-416. DOI: 10.1007/s13105-020-00747-z. View

19.

Mu M, Zuo S, Wu R, Deng K, Lu S, Zhu J . Ferulic acid attenuates liver fibrosis and hepatic stellate cell activation via inhibition of TGF-β/Smad signaling pathway. Drug Des Devel Ther. 2018; 12:4107-4115. PMC: 6284527. DOI: 10.2147/DDDT.S186726. View

20.

Al-Hashem F, Al Humayed S, Haidara M, Latif N, Al-Ani B . Captopril suppresses hepatic mammalian target of rapamycin cell signaling and biomarkers of inflammation and oxidative stress in thioacetamide-induced hepatotoxicity in rats. Arch Physiol Biochem. 2019; 127(5):414-421. DOI: 10.1080/13813455.2019.1647249. View