Recombinant truncated TGF‑β receptor II attenuates carbon tetrachloride‑induced epithelial‑mesenchymal transition and liver fibrosis in rats

Li,Luxin; Li,Hongzhi; Zhang,Zhen; Zheng,Junya; Shi,Yongping; Liu,Jieting; Cao,Yanan; Yuan,Xiaohuan; Chu,Yanhui

doi:10.3892/mmr.2017.7845

Recombinant truncated TGF‑β receptor II attenuates carbon tetrachloride‑induced epithelial‑mesenchymal transition and liver fibrosis in rats

Authors:
- Luxin Li
- Hongzhi Li
- Zhen Zhang
- Junya Zheng
- Yongping Shi
- Jieting Liu
- Yanan Cao
- Xiaohuan Yuan
- Yanhui Chu
View Affiliations

Affiliations: Heilongjiang Key Laboratory of Anti‑Fibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang, Heilongjiang 157011, P.R. China
Published online on: October 20, 2017 https://doi.org/10.3892/mmr.2017.7845
Pages: 315-321

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Liver fibrosis is a pathological process of chronic liver diseases. In particular, epithelial‑mesenchymal transition (EMT) is a major source of myofibroblast structure in liver fibrosis. The present study investigated the effects of recombinant truncated transforming growth factor‑ß receptor II (rtTGFβRII) on EMT and liver fibrosis in a carbon tetrachloride (CCl4)‑induced rat model. A total of 24 rats were randomly separated into three groups: Normal control (NC), model (CCl4) and treatment (CCl4 + rtTGFβRII) groups. Histological methods, including hematoxylin and eosin, Masson's trichrome and Sirius red staining were conducted. The activities of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured using an automatic biochemical analyzer. The mRNA expression levels of fibroblast specific protein‑1 (FSP‑1), α‑smooth muscle actin (α‑SMA), fibronectin, collagen I, vimentin and E‑cadherin were detected using reverse transcription‑quantitative polymerase chain reaction analysis. The protein levels of fibronectin, collagen I, E‑cadherin, Smad2/3 and phosphorylated (p)‑Smad2/3 were detected using western blot analysis. The expression of α‑SMA, fibronectin, vimentin and E‑cadherin in the liver tissue was detected using immunofluorescence staining. The results demonstrated that in vivo, rtTGFβRII significantly reduced the degree of liver injury, serum ALT and AST activities and liver fibrosis. These factors were associated with reduced expression of FSP‑1, α‑SMA, fibronectin, collagen I, vimentin and p‑Smad2/3, and increased expression of E‑cadherin. The results of the present study suggest that rtTGFβRII may inhibit EMT processes in CCl4‑induced liver fibrosis in rats and alter the expression of epithelial and myofibroblast markers. Therefore, rtTGFβRII may be considered a possible treatment for preventing liver fibrosis via EMT processes.

View Figures

View References

1	Zhong W, Shen WF, Ning BF, Hu PF, Lin Y, Yue HY, Yin C, Hou JL, Chen YX, Zhang JP, et al: Inhibition of extracellular signal-regulated kinase 1 by adenovirus mediated small interfering RNA attenuates hepatic fibrosis in rats. Hepatology. 50:1524–1536. 2009. View Article : Google Scholar : PubMed/NCBI
2	Bataller R and Brenner DA: Liver fibrosis. J Clin Invest. 115:209–218. 2005. View Article : Google Scholar : PubMed/NCBI
3	Zhan YY, Wang JH, Tian X, Feng SX, Xue L and Tian LP: Protective effects of seed melon extract on CCl4-induced hepatic fibrosis in mice. J Ethnopharmacol. 193:531–537. 2016. View Article : Google Scholar : PubMed/NCBI
4	Friedman SL: Mechanisms of hepatic fibrogenesis. Gastroenterology. 134:1655–1669. 2008. View Article : Google Scholar : PubMed/NCBI
5	Liu Y, Yang P, Chen N, Lin S and Liu M: Effects of recombinant human adenovirus-p53 on the regression of hepatic fibrosis. Int J Mol Med. 38:1093–1100. 2016. View Article : Google Scholar : PubMed/NCBI
6	Chen X, Ying X, Zhang W, Chen Y, Shi C, Hou Y and Zhang Y: The hepatoprotective effect of fraxetin on carbon tetrachloride induced hepatic fibrosis by antioxidative activities in rats. Int Immunopharmacol. 17:543–547. 2013. View Article : Google Scholar : PubMed/NCBI
7	Choi SS and Diehl AM: Epithelial-to-mesenchymal transitions in the liver. Hepatology. 50:2007–2013. 2009. View Article : Google Scholar : PubMed/NCBI
8	Thenappan A, Li Y, Kitisin K, Rashid A, Shetty K, Johnson L and Mishra L: Role of transforming growth factor beta signaling and expansion of progenitor cells in regenerating liver. Hepatology. 51:1373–1382. 2010. View Article : Google Scholar : PubMed/NCBI
9	Fabris L and Strazzabosco M: Epithelial-mesenchymal interactions in biliary diseases. Semin Liver Dis. 31:11–32. 2011. View Article : Google Scholar : PubMed/NCBI
10	Lee SJ, Kim KH and Park KK: Mechanisms of fibrogenesis in liver cirrhosis: The molecular aspects of epithelial-mesenchymal transition. World J Hepatol. 6:207–216. 2014. View Article : Google Scholar : PubMed/NCBI
11	Pinzani M: Epithelial-mesenchymal transition in chronic liver disease: Fibrogenesis or escape from death? J Hepatol. 55:459–465. 2011. View Article : Google Scholar : PubMed/NCBI
12	Taura K, Iwaisako K, Hatano E and Uemoto S: Controversies over the epithelial-to-mesenchymal transition in liver fibrosis. J Clinical Med. 5:pii: E9. 2016. View Article : Google Scholar
13	Wells RG: Fibrogenesis. V. TGF-beta signaling pathways. Am J Physiol Gastrointest Liver Physiol. 279:G845–G850. 2000.PubMed/NCBI
14	Verrecchia F and Mauviel A: Transforming growth factor-beta and fibrosis. World J Gastroenterol. 13:3056–3062. 2007. View Article : Google Scholar : PubMed/NCBI
15	Zavadil J and Böttinger EP: TGF-beta and epithelial-to-mesenchymal transitions. Oncogene. 24:5764–5774. 2005. View Article : Google Scholar : PubMed/NCBI
16	Fabregat I, Moreno-Càceres J, Sánchez A, Dooley S, Dewidar B, Giannelli G and Ten Dijke P: IT-LIVERConsortium: TGF-β signalling and liver disease. FEBS J. 283:2219–2232. 2016. View Article : Google Scholar : PubMed/NCBI
17	Shrestha N, Chand L, Han MK, Lee SO, Kim CY and Jeong YJ: Glutamine inhibits CCl4 induced liver fibrosis in mice and TGF-β1 mediated epithelial-mesenchymal transition in mouse hepatocytes. Food Chem Toxicol. 93:129–137. 2016. View Article : Google Scholar : PubMed/NCBI
18	Chu Y, Guo F, Li Y, Li X, Zhou T and Guo Y: A novel truncated TGF-beta receptor II downregulates collagen synthesis and TGF-beta I secretion of keloid fibroblasts. Connect Tissue Res. 49:92–98. 2008. View Article : Google Scholar : PubMed/NCBI
19	Institute for Laboratory Animal ResearchGuide for the Care and Ue of Laboratory Animals. 8th edition. National Academy Press; Washington, DC: 2011
20	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
21	Sicklick JK, Choi SS, Bustamante M, McCall SJ, Pérez EH, Huang J, Li YX, Rojkind M and Diehl AM: Evidence for epithelial-mesenchymal transitions in adult liver cells. Am J Physiol Gastrointest Liver Physiol. 291:G575–G583. 2006. View Article : Google Scholar : PubMed/NCBI
22	Rygiel KA, Robertson H, Marshall HL, Pekalski M, Zhao L, Booth TA, Jones DE, Burt AD and Kirby JA: Epithelial-mesenchymal transition contributes to portal tract fibrogenesis during human chronic liver disease. Lab Invest. 88:112–123. 2008. View Article : Google Scholar : PubMed/NCBI
23	Chen S, Zou L, Li L and Wu T: The protective effect of glycyrrhetinic acid on carbon tetrachloride-induced chronic liver fibrosis in mice via upregulation of Nrf2. PLoS One. 8:e536622013. View Article : Google Scholar : PubMed/NCBI
24	He X, Lv R, Wang K, Huang X, Wu W, Yin L and Liu Y: Cytoglobin exhibits anti-fibrosis activity on liver in vivo and in vitro. Protein J. 30:437–446. 2011. View Article : Google Scholar : PubMed/NCBI
25	Gressner OA and Gao C: Monitoring fibrogenic progression in the liver. Clin Chim Acta. 433:111–122. 2014. View Article : Google Scholar : PubMed/NCBI
26	Prud'homme GJ: Pathobiology of transforming growth factor beta in cancer, fibrosis and immunologic disease, and therapeutic considerations. Lab Invest. 87:1077–1091. 2007. View Article : Google Scholar : PubMed/NCBI
27	Li MO, Wan YY, Sanjabi S, Robertson AK and Flavell RA: Transforming growth factor-beta regulation of immune responses. Ann Rev Immunol. 24:99–146. 2006. View Article : Google Scholar
28	Rubtsov YP and Rudensky AY: TGFbeta signalling in control of T-cell-mediated self-reactivity. Nat Rev Immunol. 7:443–453. 2007. View Article : Google Scholar : PubMed/NCBI
29	Massague J: TGFβ signalling in context. Nat Rev Mol Cell Biol. 13:616–630. 2012. View Article : Google Scholar : PubMed/NCBI
30	ten Dijke P and Hill CS: New insights into TGF-β-Smad signalling. Trends Biochem Sci. 29:265–273. 2004. View Article : Google Scholar : PubMed/NCBI
31	Wynn TA and Ramalingam TR: Mechanisms of fibrosis: Therapeutic translation for fibrotic disease. Nat Med. 18:1028–1040. 2012. View Article : Google Scholar : PubMed/NCBI