Nintedanib (BIBF1120) is a triple kinase inhibitor of platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptors (FGFR), vascular endothelial growth factor receptor (VEGFR), and Src family kinase, which has recently been approved by FDA to treat idiopathic pulmonary fibrosis. Whether it affects renal fibrosis remains unknown. Here, we demonstrated that administration of nintedanib immediately or 3 days after unilateral ureteral obstruction (UUO) injury and with folic acid (FA) injection attenuated renal fibrosis and inhibited activation of renal interstitial fibroblasts. Delayed administration of nintedanib also partially reversed established renal fibrosis. Treatment with nintedanib blocked UUO-induced phosphorylation of PDGFRβ, FGFR1, FGFR2, VEGFR2, and several Src family kinases including Src, Lck, Lyn as well as activation of signal transducer and activator of transcription-3 (STAT3), nuclear factor-κB (NF-κB), and Smad-3 in the kidney. Furthermore, nintedanib inhibited UUO-elicited renal proinflammatory cytokine expression and macrophage infiltration. These data indicate that nintedanib is a potent anti-fibrotic agent in the kidney and may hold therapeutic potential as a treatment of chronic fibrotic kidney disease.
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Research Article|
July 24 2017
Nintedanib, a triple tyrosine kinase inhibitor, attenuates renal fibrosis in chronic kidney disease
Feng Liu;
Feng Liu
*
1Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
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Li Wang;
Li Wang
*
1Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
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Hualin Qi;
Hualin Qi
1Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
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Jun Wang;
Jun Wang
1Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
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Yi Wang;
Yi Wang
1Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
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Wei Jiang;
Wei Jiang
1Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
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Liuqing Xu;
Liuqing Xu
1Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
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Na Liu;
Na Liu
1Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
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Shougang Zhuang
1Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
2Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, RI, USA
Correspondence: Shougang Zhuang ([email protected])
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Publisher: Portland Press Ltd
Received:
March 01 2017
Revision Received:
June 22 2017
Accepted:
June 23 2017
Accepted Manuscript online:
June 23 2017
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2017
Clin Sci (Lond) (2017) 131 (16): 2125–2143.
Article history
Received:
March 01 2017
Revision Received:
June 22 2017
Accepted:
June 23 2017
Accepted Manuscript online:
June 23 2017
Citation
Feng Liu, Li Wang, Hualin Qi, Jun Wang, Yi Wang, Wei Jiang, Liuqing Xu, Na Liu, Shougang Zhuang; Nintedanib, a triple tyrosine kinase inhibitor, attenuates renal fibrosis in chronic kidney disease. Clin Sci (Lond) 15 August 2017; 131 (16): 2125–2143. doi: https://doi.org/10.1042/CS20170134
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