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Angiotensin‐II type 1 receptor‐mediated Janus kinase 2 activation induces liver fibrosis
Author(s) -
Granzow Michaela,
Schierwagen Robert,
Klein Sabine,
Kowallick Benita,
Huss Sebastian,
Linhart Markus,
Mazar Irela G. Reza,
Görtzen Jan,
Vogt Annabelle,
Schildberg Frank A.,
GonzalezCarmona Maria A.,
Wojtalla Alexandra,
Krämer Benjamin,
Nattermann Jacob,
Siegmund Sören V.,
Werner Nikos,
Fürst Dieter O.,
Laleman Wim,
Knolle Percy,
Shah Vijay H.,
Sauerbruch Tilman,
Trebicka Jonel
Publication year - 2014
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.27117
Subject(s) - hepatic stellate cell , angiotensin ii , fibrosis , hepatic fibrosis , rhoa , biology , receptor , cancer research , signal transduction , endocrinology , medicine , microbiology and biotechnology , chemistry
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 intracellular 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 real‐time polymerase chain reaction, western blotting, immunohistochemistry, and confocal microscopy. Experimental fibrosis was induced by bile duct ligation (BDL), CCl 4 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. (H epatology 2014;60:334–348)