Abstract: SA-PO946
Nintedanib Attenuates the Development and Progression of Peritoneal Fibrosis
Session Information
- Peritoneal Dialysis: Inflammation, Peritoneal Transport
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Dialysis
- 703 Dialysis: Peritoneal Dialysis
Authors
- Liu, Feng, Shanghai East Hospital, Shanghai, China
- Zhuang, Shougang, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, Rhode Island, United States
- Yu, Chao, Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
Background
Nintedanib, a FDA approved triple tyrosine kinase inhibitor, has antifibrotic effects in idiopathic pulmonary fibrosis and renal fibrosis.Here, we examined the effect of nintedanib on the development and progression of peritoneal fibrosis.
Methods
Daily intraperitoneal injections of chlorhexidine gluconate (CG) induced peritoneal fibrosis in mouse and TGF-β1 was used to induce fibrotic changes in cultured human peritoneal mesothelial cells. The effects of nintedanib were determined by histochemical and immunofluorescent staining, immunoblot and ELISA analysis.
Results
Administration of nintedanib immediately after injury prevented the onset of peritoneal fibrosis and delayed administration of nintedanib (3 days after the onset of peritoneal fibrosis) halted fibrosis progression.Nintedanib treatment abrogated the increased phosphorylation of PDGFR,FGFR,VEGFR,Src, decreased the expression of extracellular matrix(ECM) protein (Fibronectin and type I Collagen), inhibited the expression if marker proteins of mesenchymal phenotype (α-SMA,β-Vimentin) and transcription factors(Snail and Twist), increased expression E-Cadherin, blocked the phosphorylation of Smad3, STAT3, and NF-κB during peritoneal fibrosis; it also inhibited the accompanying overproduction of proinflammatory cytokines (MCP-1, TNF-α, IL-1β, and IL-6) and the infiltration of macrophages (CD68-positive) to the injured peritoneum, and reduced the peritoneal increase of CD31-positive blood vessels after injury.Moreover, delayed administration of nintedanib significantly induced MMP-2 expression and inhibited TIMP-2 expression. Finally, nintedanib abrogated TGF-β1–induced the epithelial-to-mesenchymal transition, ECM protein overproduction and phosphorylation of aforementioned cell signaling molecules in cultured human peritoneal mesothelial cells.
Conclusion
These results demonstrate that nintedanib may inhibit epithelial-to-mesenchymal transition, extracellular matrix overproduction inflammation and angiogenesis, and improved extracellular matrix degradation, possibly through its blockade of RTKs and Src simultaneously. It suggests that nintedanib may have therapeutic potential in attenuating onset and progression of peritoneal fibrosis.
Funding
- Government Support - Non-U.S.