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

Michaela Granzow, Robert Schierwagen, Sabine Klein, Benita Kowallick, Sebastian Huss, Markus Linhart, Irela G Reza Mazar, Jan Görtzen, Annabelle Vogt, Frank A. Schildberg, Maria A. Gonzalez-Carmona, Alexandra Wojtalla, Benjamin Krämer, Jacob Nattermann, Sören V. Siegmund, Nikos Werner, Dieter O. Fürst, Wim Laleman, Percy Knolle, Vijay ShahTilman Sauerbruch, Jonel Trebicka

Research output: Contribution to journalArticle

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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 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), 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.

Original languageEnglish (US)
Pages (from-to)334-348
Number of pages15
JournalHepatology
Volume60
Issue number1
DOIs
StatePublished - 2014

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Janus Kinase 2
Angiotensin Type 1 Receptor
Liver Cirrhosis
Hepatic Stellate Cells
Rodentia
Fibrosis
Kupffer Cells
Angiotensin II
Hepatocytes
Thioacetamide
Gene Expression
Angiotensin I
rho-Associated Kinases
Angiotensin Receptors
Wild Animals
Renin-Angiotensin System
Bile Ducts
Confocal Microscopy
Ligation
Real-Time Polymerase Chain Reaction

ASJC Scopus subject areas

  • Hepatology

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Granzow, M., Schierwagen, R., Klein, S., Kowallick, B., Huss, S., Linhart, M., ... Trebicka, J. (2014). Angiotensin-II type 1 receptor-mediated Janus kinase 2 activation induces liver fibrosis. Hepatology, 60(1), 334-348. https://doi.org/10.1002/hep.27117

Angiotensin-II type 1 receptor-mediated Janus kinase 2 activation induces liver fibrosis. / Granzow, Michaela; Schierwagen, Robert; Klein, Sabine; Kowallick, Benita; Huss, Sebastian; Linhart, Markus; Mazar, Irela G Reza; Görtzen, Jan; Vogt, Annabelle; Schildberg, Frank A.; Gonzalez-Carmona, Maria A.; Wojtalla, Alexandra; Krämer, Benjamin; Nattermann, Jacob; Siegmund, Sören V.; Werner, Nikos; Fürst, Dieter O.; Laleman, Wim; Knolle, Percy; Shah, Vijay; Sauerbruch, Tilman; Trebicka, Jonel.

In: Hepatology, Vol. 60, No. 1, 2014, p. 334-348.

Research output: Contribution to journalArticle

Granzow, M, Schierwagen, R, Klein, S, Kowallick, B, Huss, S, Linhart, M, Mazar, IGR, Görtzen, J, Vogt, A, Schildberg, FA, Gonzalez-Carmona, MA, Wojtalla, A, Krämer, B, Nattermann, J, Siegmund, SV, Werner, N, Fürst, DO, Laleman, W, Knolle, P, Shah, V, Sauerbruch, T & Trebicka, J 2014, 'Angiotensin-II type 1 receptor-mediated Janus kinase 2 activation induces liver fibrosis', Hepatology, vol. 60, no. 1, pp. 334-348. https://doi.org/10.1002/hep.27117
Granzow M, Schierwagen R, Klein S, Kowallick B, Huss S, Linhart M et al. Angiotensin-II type 1 receptor-mediated Janus kinase 2 activation induces liver fibrosis. Hepatology. 2014;60(1):334-348. https://doi.org/10.1002/hep.27117
Granzow, Michaela ; Schierwagen, Robert ; Klein, Sabine ; Kowallick, Benita ; Huss, Sebastian ; Linhart, Markus ; Mazar, Irela G Reza ; Görtzen, Jan ; Vogt, Annabelle ; Schildberg, Frank A. ; Gonzalez-Carmona, Maria A. ; Wojtalla, Alexandra ; Krämer, Benjamin ; Nattermann, Jacob ; Siegmund, Sören V. ; Werner, Nikos ; Fürst, Dieter O. ; Laleman, Wim ; Knolle, Percy ; Shah, Vijay ; Sauerbruch, Tilman ; Trebicka, Jonel. / Angiotensin-II type 1 receptor-mediated Janus kinase 2 activation induces liver fibrosis. In: Hepatology. 2014 ; Vol. 60, No. 1. pp. 334-348.
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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 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), 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.",
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AU - Granzow, Michaela

AU - Schierwagen, Robert

AU - Klein, Sabine

AU - Kowallick, Benita

AU - Huss, Sebastian

AU - Linhart, Markus

AU - Mazar, Irela G Reza

AU - Görtzen, Jan

AU - Vogt, Annabelle

AU - Schildberg, Frank A.

AU - Gonzalez-Carmona, Maria A.

AU - Wojtalla, Alexandra

AU - Krämer, Benjamin

AU - Nattermann, Jacob

AU - Siegmund, Sören V.

AU - Werner, Nikos

AU - Fürst, Dieter O.

AU - Laleman, Wim

AU - Knolle, Percy

AU - Shah, Vijay

AU - Sauerbruch, Tilman

AU - Trebicka, Jonel

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N2 - 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), 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.

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