Correlation of ursolic acid against liver fibrosis with Ang Ⅱ/AT1R signaling pathway
CHEN Tao1 LIU Cong2 WAN Si-zhe2 ZHU Xuan2▲
1. Department of Gastroenterology, Fuzhou First People′s Hospital, Jiangxi Province, Fuzhou 344099, China;
2. Department of Gastroenterology, the First Affiliated Hospital of Nanchang University, Jiangxi Province, Nanchang 330006,China
Abstract：Objective To analyze the anti-fibrotic effect of ursolic acid (UA) and its underlying mechanism based on the Ang Ⅱ/AT1R signaling pathway. Methods Forty SD rats were randomly divided into control group, model group,perindopril group and UA intervention group, with 10 rats in each group. Rats in control group were given olive oil intragastric administration, and rats in model group were induced by carbon tetrachloride solution (CCl4) to construct hepatic fibrosis model, Perindopril group and UA intervention group were given perindopril and UA respectively by intragastric administration on the basis of constructing hepatic fibrosis model of SD rats. Liver histopathology was observed by HE staining, and collagen deposition in liver was observed by Sirius red staining. Serum glutamic-oxalacetic transaminase, glutamic-pyruvic transaminase and serum total bilirubin expression levels were detected using kits. The protein expression levels of Ang Ⅱ, AT1R, Collagen Ⅰ and α -smooth muscle actin (α-SMA) in liver were detected by western blot. The mRNA expression levels of Ang Ⅱ, AT1R, Collagen Ⅰ and α-SMA were detected by real-time fluorescence quantitative polymerase chain reaction. Liver slices were scored by METAVIR hepatic fibrosis scoring system. Results The degree of inflammatory cell infiltration, balloon-like change and collagen deposition of liver in model group were higher than those in control group, the necrosis area of liver cells in the perindopril group and UA intervention group was lower than that in the model group. METAVIR score in model group was higher than that in control group, Perindopril group and UA intervention group, the differences were statistically significant(P＜0.05). The expression levels of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and total bilirubin (TBil) in model group were higher than those in control group, Perindopril group and UA intervention group,the differences were statistically significant (P＜0.05). The expressions of Ang Ⅱ, AT1R, Collagen Ⅰ and α-SMA proteins in liver of model group were higher than those in control group, Perindopril group and UA intervention group, the differences were statistically significant (P＜0.05). Conclusion UA has anti-fibrosis effect, which can significantly reduce liver inflammation, collagen deposition, and significantly alleviate the progression of liver fibrosis, which may be related to the Ang Ⅱ/AT1R signaling pathway. UA is expected to become a drug candidate for anti-fibrosis targeting the Ang Ⅱ/AT1R signaling pathway in the future.
Seki E，Brenner DA.Recent advancement of molecular mechanisms of liver fibrosis[J].J Hepatobiliary Pancreat Sci，2015，22（7）：512-518.
[5]
Marcellin P，Gane E，Buti M，et al.Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B：a 5-year open-label follow-up study[J].Lancet，2013，381（9865）：468-475.
[6]
D'Ambrosio R，Aghemo A，Rumi MG，et al.A morphometric and immunohistochemical study to assess the benefit of a sustained virological response in hepatitis C virus patients with cirrhosis[J].Hepatology，2012，56（2）：532-543.
[7]
Abd ES，Fayed HM.Targeting AngII/AT1R signaling pathway by perindopril inhibits ongoing liver fibrosis in rat[J].J Tissue Eng Regen Med，2019，13（12）：2131-2141.
[8]
Zhao R，Li T，Zheng G，et al.Simultaneous inhibition of growth and metastasis of hepatocellular carcinoma by codelivery of ursolic acid and sorafenib using lactobionic acid modified and pH-sensitive chitosan-conjugated mesoporous silica nanocomplex[J].Biomaterials，2017，143：1-16.
[9]
Fontanay S，Grare M，Mayer J，et al.Ursolic，oleanolic and betulinic acids：antibacterial spectra and selectivity indexes[J].J Ethnopharmacol，2008，120（2）：272-276.
[10]
Zhao C，Yin S，Dong Y，et al.Autophagy-dependent EIF2AK3 activation comprom ises ursolic acid-induced apoptosis through upregulation of MCL1 in MCF-7 human breast cancer cells[J].Autophagy，2013，9（2）：196-207.
[11]
Liu B，Liu Y，Yang G，et al.Ursolic acid induces neural regeneration after sciatic nerve injury[J].Neural Regen Res，2013，8（27）：2510-2519.
[12]
Wan S，Luo F，Huang C，et al.Ursolic acid reverses liver fibrosis by inhibiting interactive NOX4/ROS and RhoA/ROCK1 signalling pathways[J].Aging （Albany NY），2020，12（11）：10614-10632.
[13]
Care NRCU，Animals AUOL.Guide for the Care and Use of Laboratory Animals[M].Washington（DC）：National Academies Press （US），2011.
[14]
Poynard T，Bedossa P，Opolon P.Natural history of liver fibrosis progression in patients with chronic hepatitis C.The OBSVIRC，METAVIR，CLINIVIR，and DOSVIRC groups[J].Lancet，1997，349（9055）：825-832.
[15]
Meng Y，Song Y，Yan Z，et al.Synthesis and in vitro cytotoxicity of novel ursolic acid derivatives [J].Molecules，2010，15（6）：4033-4040.
[16]
Gan D，Zhang W，Huang C，et al.Ursolic acid ameliorates CCl4-induced liver fibrosis through the NOXs/ROS pathway[J].J Cell Physiol，2018，233（10）：6799-6813.
[17]
He W，Shi F，Zhou ZW，et al.A bioinformatic and mechanistic study elicits the antifibrotic effect of ursolic acid through the attenuation of oxidative stress with the involvement of ERK，PI3K/Akt，and p38 MAPK signaling pathways in human hepatic stellate cells and rat liver[J].Drug Des Devel Ther，2015，9：3989-4104.
[18]
Yu SS，Chen B，Huang CK，et al.Ursolic acid suppresses TGF-beta1-induced quiescent HSC activation and transformation by inhibiting NADPH oxidase expression and Hedgehog signaling[J].Exp Ther Med，2017，14（4）：3577-3582.
[19]
Forrester SJ，Booz GW，Sigmund CD，et al.Angiotensin ⅡSignal Transduction：An Update on Mechanisms of Physiology and Pathophysiology[J].Physiol Rev，2018，98（3）：1627-1738.
[20]
Bataller R，Gabele E，Schoonhoven R，et al.Prolonged infusion of angiotensin Ⅱinto normal rats induces stellate cell activation and proinflammatory events in liver[J].Am J Physiol Gastrointest Liver Physiol，2003，285（3）：G642-G651.
Lee YA，Wallace MC，Friedman SL.Pathobiology of liver fibrosis：a translational success story[J].Gut，2015，64（5）：830-841.
[3]
Zhang DY，Friedman SL.Fibrosis-dependent mechanisms of hepatocarcinogenesis[J].Hepatology，2012，56（2）：769-775.
[21]
Douillette A，Bibeau-Poirier A，Gravel SP，et al.The proinflammatory actions of angiotensin Ⅱare dependent on p65 phosphorylation by the IkappaB kinase complex[J].J Biol Chem，2006，281（19）：13275-13284.
[22]
Moreira DMS，Guimaraes TA，Feltenberger JD，et al.The role of renin-angiotensin system modulation on treatment and prevention of liver diseases[J].Peptides，2014，62：189-196.
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