Angiotensin-II type 1 receptor-mediated Janus kinase 2 activation induces liver fibrosis

Abstract

Activation of the renin angiotensin system resulting in stimulation of angiotensin-II (AngII) type I receptor (AT1R) is an important factor in the development of liver fibrosis. Here, we investigated the role of Janus kinase 2 (JAK2) as a newly described intra-cellular effector of AT1R in mediating liver fibrosis. Fibrotic liver samples from rodents and humans were compared to respective controls. Transcription, protein expression, activation, and localization of JAK2 and downstream effectors were analyzed by realtime polymerase chain reaction, western blotting, immunohistochemistry, and confocal microscopy. Experimental fibrosis was induced by bile duct ligation (BDL), CCl4 intoxication, thioacetamide intoxication or continuous AngII infusion. JAK2 was inhibited by AG490. In vitro experiments were performed with primary rodent hepatic stellate cells (HSCs), Kupffer cells (KCs), and hepatocytes as well as primary human and human-derived LX2 cells. JAK2 expression and activity were increased in experimental rodent and human liver fibrosis, specifically in myofibroblastic HSCs. AT1R stimulation in wild-type animals led to activation of HSCs and fibrosis in vivo through phosphorylation of JAK2 and subsequent RhoA/Rho-kinase activation. These effects were prevented in AT1R–/– mice. Pharmacological inhibition of JAK2 attenuated liver fibrosis in rodent fibrosis models. In vitro, JAK2 and downstream effectors showed increased expression and activation in activated HSCs, when compared to quiescent HSCs, KCs, and hepatocytes isolated from rodents. In primary human and LX2 cells, AG490 blocked AngII-induced profibrotic gene expression. Overexpression of JAK2 led to increased profibrotic gene expression in LX2 cells, which was blocked by AG490. Conclusion Our study substantiates the important cell-intrinsic role of JAK2 in HSCs for development of liver fibrosis. Inhibition of JAK2 might therefore offer a promising therapy for liver fibrosis.

Interplay of Matrix Stiffness and c-SRC in Hepatic Fibrosis

“…These effects are mediated by upregulated RhoA/Rho-kinase signaling upon liver damage (Trebicka et al, 2007(Trebicka et al, , 2010. Our group has demonstrated several times that the signaling cascade via JAK2, RhoA, and Rho-kinase signaling is upregulated in liver fibrosis and located mainly in myofibroblast-like activated HSC (Zhou et al, 2006;Granzow et al, 2014;Klein et al, 2015). With the current study we show that increased RhoA activity leads to decreased c-SRC activity with progressive HSC activation.…”

“…Rats with an initial body weight between 80 and 100 g were administered carbon tetrachloride (CCl 4 ) via inhalation for 14-16 weeks as described previously (Granzow et al, 2014). Agematched rats who did not receive CCl 4 served as controls.…”

“…Primary rat hepatocytes and hepatic stellate cells were isolated and cultured as described previously (Herman et al, 1988;Wojtalla et al, 2012;Granzow et al, 2014). Viability and purity were routinely more than 95%.…”

Synectin promotes fibrogenesis by regulating PDGFR isoforms through distinct mechanisms

“…In this regard, while advanced liver fibrosis accounts for significant morbidity and mortality through complications of portal hypertension, liver failure, and cancer, effective treatments remain to be developed. Our laboratory focuses on studying hepatic stellate cell (HSC), since they are key regulators of liver fibrosis (1)(2)(3). In response to various stimuli, HSC assume a myofibroblast phenotype characterized by increased migration, proliferation, and release of extracellular matrix proteins.…”

Hepatoprotective Effect of Eplerenone, A Selective Mineralocorticoid Receptor Antagonist, Against Thioacetamide Induced Liver Injury in Rats

“…Experimental fibrosis can be induced by bile duct ligation (BDL) and intoxication by carbon tetrachloride (CCl 4 ) or thioacetamide [5]. Thioacetamide (TAA), used as a fungicide several decades ago, is a potent hepatotoxin resulting in liver injury and centrilobular necrosis [6].…”