Abstract: SA-PO324

Targeting Src Attenuates Peritoneal Fibrosis and Inhibits Epithelial to Mesenchymal Transition of Peritoneal Mesothelial Cells

Session Information

Category: Chronic Kidney Disease (Non-Dialysis)

  • 308 CKD: Mechanisms of Tubulointerstitial Fibrosis

Authors

  • Wang, Jun, Department of Nephrology, Shanghai East Hospital, Tongji University , Shanghai , China
  • Xu, Liuqing, Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai , China
  • Liu, Na, Department of Nephrology, Shanghai East Hospital, Tongji University , Shanghai , China
  • Zhuang, Shougang, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, Rhode Island, United States
Background

Src mediates tissue fibrosis in several organs, but its role in peritoneal fibrosis remains unknown.

Methods

We evaluated the therapeutic effect of a highly selective Src inhibitor KX2-391, on development of chlorhexidine gluconate (CG)-induced peritoneal fibrosis in a rat model.

Results

Daily intraperitoneal CG injections induced peritoneal fibrosis, indicated by submesothelial collagen fibril accumulation and myofibroblast activation, accompanied by time-dependent Src phosphorylation at tyrosine 416. KX2-391 attenuated peritoneal fibrosis, abrogating increased phosphorylation of Src and multiple signaling molecules associated with tissue fibrosis, including epidermal growth factor receptor, Akt, Signal transducer and activator of transcription 3 and nuclear factor-κB in the injured peritoneum. KX2-391 inhibited proinflammatory cytokine production and macrophage infiltration of injured peritoneum. Src inhibition by KX2-391 or siRNA in cultured human peritoneal mesothelial cells led to decreased expression of α-smooth muscle actin, fibronectin and collagen I, markers of epithelial to mesenchymal transition.

Conclusion

Src may be a critical mediator of epithelial to mesenchymal transition, fibroblast activation and peritoneal fibrosis. Src could be a potential therapeutic target for treating peritoneal fibrosis.

Funding

  • Government Support - Non-U.S.