Role of DDAH/ADMA pathway in TGF-β1-mediated activation of hepatic stellate cells

Liu,Zhenguo; Wang,Juan; Xing,Wu; Peng,Yingqiong; Huang,Yan; Fan,Xuegong

doi:10.3892/mmr.2017.8107

Role of DDAH/ADMA pathway in TGF-β1-mediated activation of hepatic stellate cells

Authors:
- Zhenguo Liu
- Juan Wang
- Wu Xing
- Yingqiong Peng
- Yan Huang
- Xuegong Fan
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Affiliations: Department of Infectious Disease, Key Laboratory of Viral Hepatitis of Hunan, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China, Department of Radiology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China, Department of Infectious Disease, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China
Published online on: November 20, 2017 https://doi.org/10.3892/mmr.2017.8107
Pages: 2549-2556

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Abstract

Asymmetric dimethylarginine (ADMA) is catalyzed by the enzyme dimethylarginine dimethylaminohydrolase (DDAH) in humans, and the role for ADMA has been associated with hepatic fibrogenesis. Transforming growth factor‑β (TGF‑β) has been shown to mediate the myofibroblastic transformation of quiescent hepatic stellate cells (HSCs), a pivotal step in liver fibrogenesis. However, the underlying molecular mechanisms are not well understood. Accumulation of ADMA due to low activity of DDAH has been reported to be associated with liver damage and hepatic fibrosis. In this study, the role of the DDAH/ADMA pathway in the TGF‑β1‑induced HSC activation was assessed. Freshly harvested primary HSCs from rat liver were used in this study. It was demonstrated that TGF‑β1 treatment significantly suppressed the DDAH protein expression and activity, and increased levels of ADMA in the culture medium of rat primary HSCs. Notably, the TGF‑β1‑mediated effects on DDAH/ADMA were significantly abrogated by the p38 mitogen activated protein kinase specific inhibitor, SB203580. Furthermore, it was demonstrated that excessive ADMA led to an increase in the number of TGF‑β1‑positive HSCs and induced the expression of α‑smooth muscle actin and collagen type I in rat primary HSCs. In addition, rat primary HSCs exposed to excessive ADMA showed a significant increase in the expressions of α‑SMA and collagen type I. Finally, it was revealed that ADMA treatment promoted the proliferation of rat primary HSCs. In conclusion, the results obtained from the study suggest a potentially novel role for the ADMA/DDAH1 signaling pathway in TGF‑β1‑induced HSC activation, and along with the studies of others, suppression of the ADMA/DDAH1 pathway may be an alterative approach for the treatment of liver fibrosis.

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