Angiotensin II induces connective tissue growth factor expression in human hepatic stellate cells by a transforming growth factor \u03b2-independent mechanism

Ao Li,Jingyao Zhang,Xiao Xiao,Jun Wang,Songsong Wang,Xiaoxun Zhang,Rui Wang,Peng Li,Yitao Wang

doi:10.1038/s41598-017-08334-x

Abstract

Angiotensin II (Ang II) promotes hepatic fibrosis by increasing extracellular matrix (ECM) synthesis. Connective tissue growth factor (CTGF) plays a crucial role in the pathogenesis of hepatic fibrosis and emerges as downstream of the profibrogenic cytokine transforming growth factor-β (TGF-β). We aimed to investigate the molecular events that lead from the Ang II receptor to CTGF upregulation in human hepatic stellate cells, a principal fibrogenic cell type. Ang II produced an early, AT1 receptor-dependent stimulation of CTGF expression and induced a rapid activation of PKC and its downstream p38 MAPK, thereby activating a nuclear factor-κB (NF-κB) and Smad2/3 cross-talk pathway. Chemical blockade of NF-κB and Smad2/3 signaling synergistically diminished Ang II-mediated CTGF induction and exhibited an additive effect in abrogating the ECM accumulation caused by Ang II. Furthermore, we demonstrated that CTGF expression was essential for Ang II-mediated ECM synthesis. Interestingly, the ability of dephosphorylated, but not phosphorylated JNK to activate Smad2/3 signaling revealed a novel role of JNK in Ang II-mediated CTGF overexpression. These results suggest that Ang II induces CTGF expression and ECM accumulation through a special TGF-β-independent interaction between the NF-κB and Smad2/3 signals elicited by the AT1/PKCα/p38 MAPK pathway.

Highlights

Hepatic fibrosis is an important pathological feature of many liver diseases, which is characterized by fibroblast proliferation and excessive accumulation of extracellular matrix (ECM) components[1]
The main finding of the current study was that angiotensin II (Ang II) could induce a rapid expression of Connective tissue growth factor (CTGF) in human Hepatic stellate cells (HSCs) directly via the Ang II type 1 receptor (AT1) receptor-mediated PKCα activation, which driven an early p38 mitogen-activated protein kinase (MAPK)-mediated Smad and nuclear factor-κB (NF-κB) cross-talk pathway, in addition to a late transforming growth factor-β (TGF-β)-dependent mechanism
Accumulating evidence indicates that upregulation of CTGF might represent a pivotal pathway during HSC activation and hepatic fibrosis, because it plays a central role as a mitogen, fibroblast chemoattractant, and inducer of ECM component synthesis and secretion in fibrotic liver[6]

Summary

Introduction

Hepatic fibrosis is an important pathological feature of many liver diseases, which is characterized by fibroblast proliferation and excessive accumulation of extracellular matrix (ECM) components[1]. Several substances, especially endothelin-1 and platelet-derived growth factor, can stimulate the secretion of mature angiotensin II (Ang II) stored in activated HSCs9. This locally produced Ang II has proinflammatory and profibrogenic effects on HSCs10. PKC activation induces phosphorylation and activation of mitogen-activated protein kinase (MAPK) family, including c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 MAPK in HSCs, which are among the major mediators of the profibrotic effects induced by Ang II, leading to fibrotic-related gene transcription and connective tissue formation in fibrotic disorders[18]

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