Fyn deficiency attenuates renal fibrosis by inhibition of phospho-STAT3.
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-β 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, α-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 α-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.
Department of Internal Medicine, Keimyung University School of Medicine, Daegu, South Korea; Institute for Medical Science, Keimyung University School of Medicine, Daegu, South Korea.
Hye-Young
HY
Seo
Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, South Korea.
Jae-Han
JH
Jeon
Department of Internal Medicine, Keimyung University School of Medicine, Daegu, South Korea; Institute for Medical Science, Keimyung University School of Medicine, Daegu, South Korea.
Yun-A
YA
Jung
Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, South Korea.
Gwon-Soo
GS
Jung
Department of Internal Medicine, Keimyung University School of Medicine, Daegu, South Korea; Institute for Medical Science, Keimyung University School of Medicine, Daegu, South Korea.
Eun Ju
EJ
Lee
Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, South Korea.
Young-Keun
YK
Choi
Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, South Korea.
Keun-Gyu
KG
Park
Department of Pathology, Keimyung University School of Medicine, Daegu, South Korea.
Mi Sun
MS
Choe
Department of Internal Medicine, Keimyung University School of Medicine, Daegu, South Korea; Institute for Medical Science, Keimyung University School of Medicine, Daegu, South Korea.
Byoung Kuk
BK
Jang
Department of Internal Medicine, Keimyung University School of Medicine, Daegu, South Korea; Institute for Medical Science, Keimyung University School of Medicine, Daegu, South Korea. Electronic address: mdkmk@dsmc.or.kr.
Mi-Kyung
MK
Kim
Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, South Korea. Electronic address: leei@knu.ac.kr.
In-Kyu
IK
Lee
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D006801:Humans; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009400:Nephrosclerosis / Q000209:etiology / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D051900:Smad3 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014517:Ureteral Obstruction / Q000150:complications; D019061:src-Family Kinases / Q000378:metabolism
D015820:Cadherins; D016326:Extracellular Matrix Proteins; D050796:STAT3 Transcription Factor; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; C494087:Stat3 protein, mouse; D016212:Transforming Growth Factor beta; C541485:EGFR protein, mouse; D066246:ErbB Receptors; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D055372:AMP-Activated Protein Kinases
TGF-β; fibrosis; obstructive nephropathy