Publication Date:
2014-03-12
Description:
Activation of the renin-angiotensin-system resulting in stimulation of angiotensin-II-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 intracellular effector of AT1R in mediating liver fibrosis. Methods: 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 RT-PCR, Western blot, immunohistochemistry and confocal microscopy. Experimental fibrosis was induced by bile duct ligation (BDL), CCl 4 intoxication (CCl 4 ), TAA intoxication or continuous angiotensin-II infusion. JAK2 was inhibited by AG490. In vitro experiments were performed with primary rodent hepatic stellate cells (HSC), Kupffer cells and hepatocytes as well as primary human and human derived LX2 cells. Results: JAK2 expression and activity were increased in experimental rodent and human liver fibrosis, specifically in myofibroblastic hepatic stellate cells (HSC). AT1R stimulation in wild type animals led to activation of HSC and to fibrosis in vivo via phosphorylation of JAK2 and subsequent RhoA/Rho-kinase. 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 HSC when compared to quiescent HSC, Kupffer cells and hepatocytes isolated from rodents. In primary human and LX2 cells, AG490 blocked the angiotensin II 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 hepatic stellate cells for development of liver fibrosis. Inhibition of JAK2 might therefore offer a promising therapy for liver fibrosis. (H epatology 2014;)
Print ISSN:
0270-9139
Electronic ISSN:
1527-3350
Topics:
Medicine
Permalink