Angiotensin II increases mRNA levels of all TGF‐β isoforms in quiescent and activated rat hepatic stellate cells

Abstract

AII (angiotensin II) is a vasoactive peptide that plays an important role in the development of liver fibrosis mainly by regulating profibrotic cytokine expression such as TGF-beta (transforming growth factor-beta). Activated HSCs (hepatic stellate cells) are the major cell type responsible for ECM (extracellular matrix) deposition during liver fibrosis and are also a target for AII and TGF-beta actions. Here, we studied the effect of AII on the mRNA levels of TGF-beta isoforms in primary cultures of rat HSCs. Both quiescent and activated HSCs were stimulated with AII for different time periods, and mRNA levels of TGF-beta1, TGF-beta2 and TGF-beta3 isoforms were evaluated using RNaseI protection assay. The mRNA levels of all TGF-beta isoforms, particularly TGF-beta2and TGF-beta3, were increased after AII treatment in activated HSCs. In addition, activated HSCs were able to produce active TGF-beta protein after AII treatment. The mRNA expression of TGF-beta isoforms induced by AII required both ERK1/2 and Nox (NADPH oxidase) activation but not PKC (protein kinase C) participation. ERK1/2 activation induced by AII occurs via AT1 receptors, but independently of either PKC and Nox activation or EGFR (epidermal growth factor receptor) transactivation. Interestingly, AII has a similar effect on TGF-beta expression in quiescent HSCs, although it has a smaller but significant effect on ERK1/2 activation in these cells.

Salvianolic Acid B Attenuates Rat Hepatic Fibrosis via Downregulating Angiotensin II Signaling

“…TGF- β is one of the most potent profibrogenic cytokines known for activated HSC. Ang II could increase mRNA levels of all TGF- β isoforms in rat HSC [39]. In our previous study, we found that Sal B could inhibit TGF- β 1 expressions and its receptor in fibrotic livers [14] and inhibit MAPK function in activated rat HSC [40].…”

Epithelial-mesenchymal transition in liver fibrosis

“…As it responds to Smad, the further matrix production in HSCs differs between acute and chronic injury (3). In addition to TGF-β, there are numerous other factors that exhibit profibrogenic effects on HSCs, such as retinoids and angiotensin II (4)(5)(6). During liver fibrosis, parenchymal injury and sustained inflammation generate a large panel of signals that induce the activation of quiescent HSCs.…”

Role of the renin-angiotensin system in hepatic fibrosis and portal hypertension

“…HSCs are activated by reactive oxygen species, whereas fibrosis after liver injury is ameliorated in p47phox knockout mice [ 50 ]. In addition, in both activated and quiescent rat HSCs exposed to Ang II, the mRNA and protein levels of all TGF-β isoforms are upregulated via the ERK1/2- and Nox-dependent pathways, but independently of protein kinase C [ 52 ].…”