期刊
KIDNEY INTERNATIONAL
卷 90, 期 6, 页码 1285-1297出版社
NATURE PUBLISHING GROUP
DOI: 10.1016/j.kint.2016.06.038
关键词
fibrosis; obstructive nephropathy; TGF-beta
资金
- National Research Foundation of Korea (NRF) - Korean government (MSIP) [2012R1A2A1A03670452]
- Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Education, Science and Technology [2012R1A1A1010047, 2015R1C1A2A01052054]
- Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) - Ministry of Health and Welfare, Republic of Korea [HI16C1501]
- National Research Foundation of Korea [2012R1A2A1A03670452, 2012R1A1A1010047, 2015R1C1A2A01052054] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
The hallmark of renal tubulointerstitial fibrosis is the accumulation of myofibroblasts and extracellular matrix proteins. Fyn, a member of the Src family of kinases, has diverse biological functions including regulation of mitogenic signaling and proliferation and integrin-mediated interaction. Src family proteins promote pulmonary fibrosis by augmenting transforming growth factor-beta signaling, but their role in renal fibrosis is less understood. We observed upregulation of Fyn in a renal fibrosis model induced by unilateral ureteral obstruction. Upon ureteral obstruction, Fyn-deficient mice exhibited attenuated renal fibrosis relative to wild-type mice. Furthermore, obstruction-induced renal expression of type I collagen, fibronectin, alpha-smooth muscle actin, and plasminogen activator inhibitor-1 was suppressed. Pharmacologic inhibition of Fyn blocked induction of extracellular matrix proteins in kidney cell lines. Importantly, the attenuation of renal fibrosis by Fyn deficiency was not accompanied by changes in the Smad pathway. Rather, the antifibrotic effect of Fyn deficiency was associated with downregulation of signal transducer and activator of transcription 3 (STAT3). Small, interfering RNA targeting STAT3 in Fyn-deficient cells further suppressed alpha-smooth muscle actin expression, whereas a STAT3 activator partially restored plasminogen activator inhibitor-1 expression, indicating that STAT3 signaling is critically involved in this process. Thus, Fyn plays an important role in renal fibrosis. Hence, Fyn kinase inhibitors may be therapeutically useful against renal fibrosis.
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