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Fyn deficiency attenuates renal fibrosis by inhibition of phospho-STAT3
Hye-Young Seo1, Jae-Han Jeon2, Yun-A Jung1
1Department of Internal Medicine, Keimyung University School of Medicine, Daegu, South Korea; Institute for Medical Science, Keimyung University School of Medicine, Daegu, South Korea.
Abstract:
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.
Insights
Fyn kinase promotes kidney fibrosis by increasing extracellular matrix proteins via STAT3 signaling. Inhibiting Fyn kinase may offer a therapeutic strategy for treating renal fibrosis.
Area of Science:
- Nephrology
- Molecular Biology
- Biochemistry
Background:
- Renal tubulointerstitial fibrosis is characterized by myofibroblast accumulation and extracellular matrix deposition.
- Fyn kinase, a Src family kinase, regulates cell signaling and proliferation, but its role in kidney fibrosis is unclear.
- While Src family kinases are implicated in pulmonary fibrosis, their specific contribution to renal fibrosis requires further investigation.
Purpose of the Study:
- To investigate the role of Fyn kinase in the development of renal tubulointerstitial fibrosis.
- To elucidate the molecular mechanisms underlying Fyn's involvement in kidney fibrosis.
- To assess the therapeutic potential of Fyn inhibition for renal fibrosis.
Main Methods:
- Utilized a mouse model of unilateral ureteral obstruction to induce renal fibrosis.
- Compared renal fibrosis development and molecular markers in Fyn-deficient and wild-type mice.
- Employed pharmacologic inhibition and small interfering RNA (siRNA) targeting Fyn and STAT3 in kidney cell lines.
Main Results:
- Fyn kinase expression was upregulated in the renal fibrosis model.
- Fyn-deficient mice showed significantly attenuated renal fibrosis and reduced expression of collagen I, fibronectin, α-smooth muscle actin, and plasminogen activator inhibitor-1.
- Pharmacologic Fyn inhibition blocked extracellular matrix protein induction in kidney cells.
- The antifibrotic effects of Fyn deficiency were linked to the downregulation of signal transducer and activator of transcription 3 (STAT3) signaling, independent of the Smad pathway.
Conclusions:
- Fyn kinase plays a significant role in promoting renal tubulointerstitial fibrosis.
- Fyn kinase promotes renal fibrosis through STAT3 signaling pathway.
- Fyn kinase inhibitors represent a potential therapeutic avenue for treating kidney fibrosis.
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