Angiotensin II induces connective tissue growth factor expression in human hepatic stellate cells by a transforming growth factor β-independent mechanism
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...
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| Autores principales: | , , , , , , , , |
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| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Nature Portfolio
2017
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| Materias: | |
| Acceso en línea: | https://doaj.org/article/08863808e11145458c7bd94c35e10d45 |
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| Sumario: | 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. |
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