Skip to main content

Advertisement

SpringerLink
Log in

Angiotensin II Induces Endothelin-1 Expression in Human Hepatic Stellate Cells

  • Original Article
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

Background

Both angiotensin (Ang)-II and endothelin-1 (ET-1) are involved in the pathogenesis of liver fibrosis. Activated hepatic stellate cells (HSCs) are considered a key effector of liver fibrosis.

Aims

To explore the effect of Ang-II on ET-1 expression in cultured human HSCs and the underlying mechanisms.

Methods

Human HSCs were treated with Ang-II in different concentrations (0.1, 0.5, 1, 5, or 10 nM) for different lengths of time (0.5, 1, 2, 4, or 6 h) with or without transcription inhibitor actinomycin D, Ang-II type 1 (AT1) receptor blocker losartan, AT2 receptor blocker PD123177, or different kinase inhibitors.

Results

Ang-II increased the ET-1 mRNA level in a statistically significant dose- and time-dependent manner within 4 h, which led to dose-dependent up-regulation of the ET-1 protein level. Actinomycin D (1 mg/ml), losartan (50 μM), and phosphatidylinositol-3 kinase inhibitor LY294002 (50 μM) abolished the promoting effect of Ang-II on ET-1 expression. Ang-II (10 nM) significantly increased the expression of α-smooth muscle actin and type I collagen in HSCs, which was abolished by losartan, LY294002, ET A receptor blocker BQ123, and ET-1 siRNA, but not PD123177 and ET B receptor blocker BQ788.

Conclusions

Ang-II induces ET-1 expression in human HSCs via the AT1 receptor by the PI3 K/Akt signaling pathway. The ET-1/ET A receptor axis could mediate the promoting effects of Ang-II on HSCs’ transdifferentiation into myofibroblast-like cells. This is the first evidence of crosstalk between the Ang-II/AT1 axis and the ET-1 system in regard to the pathogenesis of liver fibrosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Bataller R, Brenner DA. Liver fibrosis. J Clin Invest. 2005;115:209–218.

    PubMed  CAS  Google Scholar 

  2. Arthur MJ. Reversibility of liver fibrosis and cirrhosis following treatment for hepatitis C. Gastroenterology. 2002;122:1525–1528.

    Article  PubMed  Google Scholar 

  3. Lim YS, Kim WR. The global impact of hepatic fibrosis and end-stage liver disease. Clin Liver Dis. 2008;12:733–746.

    Article  PubMed  Google Scholar 

  4. Munshi MK, Uddin MN, Glaser SS. The role of the renin-angiotensin system in liver fibrosis. Exp Biol Med (Maywood). 2011;236:557–566.

    Article  CAS  Google Scholar 

  5. Nabeshima Y, Tazuma S, Kanno K, et al. Anti-fibrogenic function of angiotensin II type 2 receptor in CCl4-induced liver fibrosis. Biochem Biophys Res Commun. 2006;346:658–664.

    Article  PubMed  CAS  Google Scholar 

  6. Bataller R, Sancho-Bru P, Gine`s P, Brenner DA. Liver fibrogenesis: a new role for the renin-angiotensin system. Antioxid Redox Signal. 2005;7:1346–1355.

    Article  PubMed  CAS  Google Scholar 

  7. Yang L, Bataller R, Dulyx J, et al. Attenuated hepatic inflammation and fibrosis in angiotensin type 1a receptor deficient mice. J Hepatol. 2005;43:317–323.

    Article  PubMed  CAS  Google Scholar 

  8. Bataller R, Gines P, Nicolas JM, et al. Angiotensin II induces contraction and proliferation of human hepatic stellate cells. Gastroenterology. 2000;118:1149–1156.

    Article  PubMed  CAS  Google Scholar 

  9. Rockey DC. Vascular mediators in the injured liver. Hepatology. 2003;37:4–12.

    Article  PubMed  CAS  Google Scholar 

  10. Pinzani M, Milani S, De Franco R, et al. Endothelin 1 is overexpressed in human cirrhotic liver and exerts multiple effects on activated hepatic stellate cells. Gastroenterology. 1996;110:534–548.

    Article  PubMed  CAS  Google Scholar 

  11. Rockey DC, Fouassier L, Chung JJ, et al. Cellular localization of endothelin-1 and increased production in liver injury in the rat: potential for autocrine and paracrine effects on stellate cells. Hepatology. 1998;27:472–480.

    Article  PubMed  CAS  Google Scholar 

  12. Li J, Kuruba R, Wilson A, Gao X, Zhang Y, Li S. Inhibition of endothelin-1-mediated contraction of hepatic stellate cells by FXR ligand. PLoS One. 2010;5:e13955.

    Article  PubMed  Google Scholar 

  13. Saward L, Zahradka P. Angiotensin II activates phosphatidylinositol 3-kinase in vascular smooth muscle cells. Circ Res. 1997;81:249–257.

    Article  PubMed  CAS  Google Scholar 

  14. Yano N, Suzuki D, Endoh M, Zhao TC, Padbury JF, Tseng YT. A novel phosphoinositide 3-kinase-dependent pathway for angiotensin II/AT-1 receptor-mediated induction of collagen synthesis in MES-13 mesangial cells. J Biol Chem. 2007;282:18819–18830.

    Article  PubMed  CAS  Google Scholar 

  15. Tian B, Liu J, Bitterman P, Bache RJ. Angiotensin II modulates nitric oxide-induced cardiac fibroblast apoptosis by activation of AKT/PKB. Am J Physiol Heart Circ Physiol. 2003;285:H1105–H1112.

    PubMed  CAS  Google Scholar 

  16. Kim YJ, Koo TY, Yang WS, et al. Activation of spleen tyrosine kinase is required for TNF-α-induced endothelin-1 upregulation in human aortic endothelial cells. FEBS Lett. 2012;586:818–826.

    Article  PubMed  CAS  Google Scholar 

  17. Carpino G, Morini S, Ginanni Corradini S, et al. Alpha-SMA expression in hepatic stellate cells and quantitative analysis of hepatic fibrosis in cirrhosis and in recurrent chronic hepatitis after liver transplantation. Dig Liver Dis. 2005;37:349–356.

    Article  PubMed  CAS  Google Scholar 

  18. Williams EJ, Benyon RC, Trim N, et al. Relaxin inhibits effective collagen deposition by cultured hepatic stellate cells and decreases rat liver fibrosis in vivo. Gut. 2001;49:577–583.

    Article  PubMed  CAS  Google Scholar 

  19. Bataller R, Brenner DA. Activated hepatic stellate cells as a target for the treatment of liver fibrosis. Semin Liver Dis. 2001;21:437–451.

    Article  PubMed  CAS  Google Scholar 

  20. Bataller R, Sancho-Bru P, Ginès P, et al. Activated human hepatic stellate cells express the renin-angiotensin system and synthesize angiotensin II. Gastroenterology. 2003;125:117–125.

    Article  PubMed  CAS  Google Scholar 

  21. Schneider AW, Kalk JF, Klein CP. Effect of losartan, an angiotensin II receptor antagonist, on portal pressure in cirrhosis. Hepatology. 1999;29:334–339.

    Article  PubMed  CAS  Google Scholar 

  22. Rockey DC, Chung JJ. Endothelin antagonism in experimental hepatic fibrosis. Implications for endothelin in the pathogenesis of wound healing. J Clin Invest. 1996;98:1381–1388.

    Article  PubMed  CAS  Google Scholar 

Download references

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Department of General Surgery, Second Xiangya Hospital, Central South University, 139 People’s Road, Changsha, 410011, Hunan, People’s Republic of China

    Chao He, Xiongying Miao, Jiequn Li & Haizhi Qi

Authors
  1. Chao He
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiongying Miao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jiequn Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Haizhi Qi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Haizhi Qi.

Electronic supplementary material

Below is the link to the electronic supplementary material.

10620_2013_2685_MOESM1_ESM.tif

Supplementary Fig. S1. Western blot analysis of endothelin-1 (ET-1) expression in human hepatic stellate cells (HSCs) treated with ET-1 siRNA. a Human HScs transfected with control siRNA or ET-1 siRNA were treated with or without angiotensin (Ang)-II (10 nM) for 4 hours. Twenty-four hours later, cell lysates were subject to western blot analyses for ΕΤ-1 expression. Lysates from human Hscs transfected with control siRNA were used as a control (lane 1). Lane 2 ET-1 siRNA; lane 3 Ang-II (10 nM)+control siRNA; lane 4 Ang-II (10 nM)+ET-1 siRNA. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) blotting was used as a loading control. b ΕΤ-1 and GAPDH blots were measured by densitometry. The density of the ΕΤ−1 blot was normalized against that of GAPDH to obtain a relative density, which was expressed as fold changes to that of control cells (designated as 1). *P < 0.05 compared with control cells. (TIFF 122 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

He, C., Miao, X., Li, J. et al. Angiotensin II Induces Endothelin-1 Expression in Human Hepatic Stellate Cells. Dig Dis Sci 58, 2542–2549 (2013). https://doi.org/10.1007/s10620-013-2685-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-013-2685-y

Keywords

Search

Navigation