Effects of renalase deficiency on liver fibrosis markers in a nonalcoholic steatohepatitis mouse model

Tokinoya,Katsuyuki; Sekine,Nanami; Aoki,Kai; Ono,Seiko; Kuji,Tomoaki; Sugasawa,Takehito; Yoshida,Yasuko; Takekoshi,Kazuhiro

doi:10.3892/mmr.2021.11849

Effects of renalase deficiency on liver fibrosis markers in a nonalcoholic steatohepatitis mouse model

Authors:
- Katsuyuki Tokinoya
- Nanami Sekine
- Kai Aoki
- Seiko Ono
- Tomoaki Kuji
- Takehito Sugasawa
- Yasuko Yoshida
- Kazuhiro Takekoshi
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Affiliations: Doctoral Program in Sports Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki 305‑8577, Japan, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki 305‑8574, Japan, Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305‑8577, Japan, Department of Clinical Laboratory Science, Faculty of Health Sciences, Tsukuba International University, Tsuchiura, Ibaraki 300‑0051, Japan
Published online on: January 18, 2021 https://doi.org/10.3892/mmr.2021.11849
Article Number: 210
Copyright: © Tokinoya et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Progression of nonalcoholic steatohepatitis (NASH) is attributed to several factors, including inflammation and oxidative stress. In recent years, renalase has been reported to suppress oxidative stress, apoptosis and inflammation. A number of studies have suggested that renalase may be associated with protecting the liver from injury. The present study aimed to clarify the effects of renalase knockout (KO) in mice with NASH that were induced with a choline‑deficient high‑fat diet (CDAHFD) supplemented with 0.1% methionine. Wild type (WT) and KO mice (6‑week‑old) were fed a normal diet (ND) or CDAHFD for 6 weeks, followed by analysis of the blood liver function markers and liver tissues. CDAHFD intake was revealed to increase blood hepatic function markers, lipid accumulation and oxidative stress compared with ND, but no significant differences were observed between the WT and KO mice. However, in the KO‑CDAHFD group, the Adgre1 and Tgfb1 mRNA levels were significantly higher, and α‑SMA expression was significantly lower compared with the WT‑CDAHFD group. Furthermore, the Gclc mRNA and phosphorylated protein kinase B (Akt) levels were significantly lower in the KO‑ND group compared with the WT‑ND group. The results of the current study indicated that as NASH progressed in the absence of renalase, oxidative stress, macrophage infiltration and TGF‑β expression were enhanced, while α‑SMA expression in NASH may be partly suppressed due to the decreased phosphorylation of Akt level.

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1	Bugianesi E, Leone N, Vanni E, Marchesini G, Brunello F, Carucci P, Musso A, De Paolis P, Capussotti L, Salizzoni M, et al: Expanding the natural history of nonalcoholic steatohepatitis: From cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology. 123:134–140. 2002. View Article : Google Scholar : PubMed/NCBI
2	Esler WP and Bence KK: Metabolic Targets in Nonalcoholic Fatty Liver Disease. Cell Mol Gastroenterol Hepatol. 8:247–267. 2019. View Article : Google Scholar : PubMed/NCBI
3	Tilg H and Moschen AR: Evolution of inflammation in nonalcoholic fatty liver disease: The multiple parallel hits hypothesis. Hepatology. 52:1836–1846. 2010. View Article : Google Scholar : PubMed/NCBI
4	Day CP and James OFW: Steatohepatitis: A tale of two ‘hits’? Gastroenterology. 114:842–845. 1998. View Article : Google Scholar : PubMed/NCBI
5	Anty R and Gual P: Pathogenesis of non-alcoholic fatty liver disease. Presse Med. 48:1468–1483. 2019.(In French). View Article : Google Scholar : PubMed/NCBI
6	Takatani N, Kono Y, Beppu F, Okamatsu-Ogura Y, Yamano Y, Miyashita K and Hosokawa M: Fucoxanthin inhibits hepatic oxidative stress, inflammation, and fibrosis in diet-induced nonalcoholic steatohepatitis model mice. Biochem Biophys Res Commun. 528:305–310. 2020. View Article : Google Scholar : PubMed/NCBI
7	Ke Z, Zhao Y, Tan S, Chen H, Li Y, Zhou Z and Huang C: Citrus reticulata Blanco peel extract ameliorates hepatic steatosis, oxidative stress and inflammation in HF and MCD diet-induced NASH C57BL/6 J mice. J Nutr Biochem. 83:1084262020. View Article : Google Scholar : PubMed/NCBI
8	Suga T, Yamaguchi H, Ogura J, Shoji S, Maekawa M and Mano N: Altered bile acid composition and disposition in a mouse model of non-alcoholic steatohepatitis. Toxicol Appl Pharmacol. 379:1146642019. View Article : Google Scholar : PubMed/NCBI
9	Matsumoto M, Hada N, Sakamaki Y, Uno A, Shiga T, Tanaka C, Ito T, Katsume A and Sudoh M: An improved mouse model that rapidly develops fibrosis in non-alcoholic steatohepatitis. Int J Exp Pathol. 94:93–103. 2013. View Article : Google Scholar : PubMed/NCBI
10	Xu J, Li G, Wang P, Velazquez H, Yao X, Li Y, Wu Y, Peixoto A, Crowley S and Desir GV: Renalase is a novel, soluble monoamine oxidase that regulates cardiac function and blood pressure. J Clin Invest. 115:1275–1280. 2005. View Article : Google Scholar : PubMed/NCBI
11	Wu Y, Xu J, Velazquez H, Wang P, Li G, Liu D, Sampaio-Maia B, Quelhas-Santos J, Russell K, Russell R, et al: Renalase deficiency aggravates ischemic myocardial damage. Kidney Int. 79:853–860. 2011. View Article : Google Scholar : PubMed/NCBI
12	Wang F, Huang B, Li J, Liu L and Wang N: Renalase might be associated with hypertension and insulin resistance in type 2 diabetes. Ren Fail. 36:552–556. 2014. View Article : Google Scholar : PubMed/NCBI
13	Wang L, Velazquez H, Chang J, Safirstein R and Desir GV: Identification of a receptor for extracellular renalase. PLoS One. 10:e01229322015. View Article : Google Scholar : PubMed/NCBI
14	Wang Y, Safirstein R, Velazquez H, Guo XJ, Hollander L, Chang J, Chen TM, Mu JJ and Desir GV: Extracellular renalase protects cells and organs by outside-in signalling. J Cell Mol Med. 21:1260–1265. 2017. View Article : Google Scholar : PubMed/NCBI
15	Wu Y, Wang L, Deng D, Zhang Q and Liu W: Renalase protects against renal fibrosis by inhibiting the activation of the ERK signaling pathways. Int J Mol Sci. 18:1–25. 2017.
16	Li H, Guo J, Liu H, Niu Y, Wang L, Huang K and Wang J: Renalase as a novel biomarker for evaluating the severity of hepatic ischemia-reperfusion injury. Oxid Med Cell Longev. 2016:31785622016. View Article : Google Scholar : PubMed/NCBI
17	Zhang T, Gu J, Guo J, Chen K, Li H and Wang J: Renalase attenuates mouse fatty liver ischemia/reperfusion injury through mitigating oxidative stress and mitochondrial damage via activating SIRT1. Oxid Med Cell Longev. 2019:75342852019. View Article : Google Scholar : PubMed/NCBI
18	Nagate T, Chino T, Nishiyama C, Okuhara D, Tahara T, Maruyama Y, Kasahara H, Takashima K, Kobayashi S, Motokawa Y, et al: Diluted isoflurane as a suitable alternative for diethyl ether for rat anaesthesia in regular toxicology studies. J Vet Med Sci. 69:1137–1143. 2007. View Article : Google Scholar : PubMed/NCBI
19	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2-ΔΔCT method. Methods. 2001.25((4)): 402–408, doi:10.1006/meth.2001.1262. View Article : Google Scholar : PubMed/NCBI
20	Kikugawa K, Yasuhara Y, Ando K, Koyama K, Hiramoto K and Suzuki M: Effect of supplementation of n-3 polyunsaturated fatty acids on oxidative stress-induced DNA damage of rat hepatocytes. Biol Pharm Bull. 26:1239–1244. 2003. View Article : Google Scholar : PubMed/NCBI
21	Zhao B, Zhao Q, Li J, Xing T, Wang F and Wang N: Renalase protects against contrast-induced nephropathy in Sprague-Dawley rats. PLoS One. 10:e01165832015. View Article : Google Scholar : PubMed/NCBI
22	Ghani MA, Barril C, Bedgood DR Jr and Prenzler PD: Measurement of antioxidant activity with the thiobarbituric acid reactive substances assay. Food Chem. 230:195–207. 2017. View Article : Google Scholar : PubMed/NCBI
23	Palladini G, Di Pasqua LG, Berardo C, Siciliano V, Richelmi P, Perlini S, Ferrigno A and Vairetti M: Animal models of steatosis (NAFLD) and steatohepatitis (NASH) exhibit hepatic lobe-specific gelatinases activity and oxidative stress. Can J Gastroenterol Hepatol. 2019:54134612019. View Article : Google Scholar : PubMed/NCBI
24	Horas H, Nababan S, Nishiumi S, Kawano Y, Kobayashi T, Yoshida M and Azuma T and Azuma T: Adrenic acid as an inflammation enhancer in non-alcoholic fatty liver disease. Arch Biochem Biophys. 623-624:64–75. 2017. View Article : Google Scholar : PubMed/NCBI
25	Chen Y, Dong H, Thompson DC, Shertzer HG, Nebert DW and Vasiliou V: Glutathione defense mechanism in liver injury: Insights from animal models. Food Chem Toxicol. 60:38–44. 2013. View Article : Google Scholar : PubMed/NCBI
26	Cha JY, Kim DH and Chun KH: The role of hepatic macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Lab Anim Res. 34:133–139. 2018. View Article : Google Scholar : PubMed/NCBI
27	Wu Y, Wang L, Wang X, Wang Y, Zhang Q and Liu W: Renalase contributes to protection against renal fibrosis via inhibiting oxidative stress in rats. Int Urol Nephrol. 50:1347–1354. 2018. View Article : Google Scholar : PubMed/NCBI
28	Huang Z, Li Q, Yuan Y, Zhang C, Wu L, Liu X, Cao W, Guo H, Duan S, Xu X, et al: Renalase attenuates mitochondrial fission in cisplatin-induced acute kidney injury via modulating sirtuin-3. Life Sci. 222:78–87. 2019. View Article : Google Scholar : PubMed/NCBI
29	Cai CX, Buddha H, Castelino-Prabhu S, Zhang Z, Britton RS, Bacon BR and Neuschwander-Tetri BA: Activation of insulin-PI3K/Akt-p70S6K pathway in hepatic stellate cells contributes to fibrosis in nonalcoholic steatohepatitis. Dig Dis Sci. 62:968–978. 2017. View Article : Google Scholar : PubMed/NCBI
30	Xu F, Liu C, Zhou D and Zhang L: TGF-β/SMAD Pathway and Its Regulation in Hepatic Fibrosis. J Histochem Cytochem. 64:157–167. 2016. View Article : Google Scholar : PubMed/NCBI
31	Ma L, Li H, Zhang S, Xiong X, Chen K, Jiang P, Jiang K and Deng G: Emodin ameliorates renal fibrosis in rats via TGF-β1/Smad signaling pathway and function study of Smurf 2. Int Urol Nephrol. 50:373–382. 2018. View Article : Google Scholar : PubMed/NCBI
32	Lv Y, Bing Q, Lv Z, Xue J, Li S, Han B, Yang Q, Wang X and Zhang Z: Imidacloprid-induced liver fibrosis in quails via activation of the TGF-β1/Smad pathway. Sci Total Environ. 705:1359152020. View Article : Google Scholar : PubMed/NCBI