Blockade of thrombospondin‐1 ameliorates high glucose‐induced peritoneal fibrosis through downregulation of TGF‐β1/Smad3 signaling pathway. Issue 1 (24th June 2019)

• Record Type: Journal Article
• Authors: Jiang, Na; Zhang, Zhen; Shao, Xinghua; Jing, Ran; Wang, Chunlin; Fang, Wei; Mou, Shan; Ni, Zhaohui
• Is Part Of: Journal of cellular physiology. Volume 235:Issue 1(2020:Jan.)
• Page Start: 364
• Page End: 379
• Publication Date: 2019-06-24
• Subjects: mesothelial‐to‐mesenchymal transition -- peritoneal dialysis -- peritoneal fibrosis -- thrombospondin‐1 -- transforming growth factor‐β1; Physiology -- Periodicals; Cell physiology -- Periodicals; 571.6
• DOI: 10.1002/jcp.28976
• Languages: English
• ISSNs: 0021-9541

Abstract

Abstract: Background: Transforming growth factor‐β1 (TGF‐β1) is a profibrotic cytokine which induces mesothelial cell mesothelial‐to‐mesenchymal transition (MMT) and peritoneal fibrosis in patients receiving treatment of peritoneal dialysis. Because thrombospondin‐1 (TSP‐1) is able to activate latent TGF‐β1 in vivo, we investigated whether blockade of TSP‐1 could modulate mesothelial cell MMT and ameliorate peritoneal fibrosis. Methods: Human pleural mesothelial cells (Met‐5A cells) were treated with TSP‐1 and addition of TGF‐β1 neutralizing antibody to assess the effect of TSP‐1 on MMT. Furthermore, TSP‐1 blocking peptide Leu‐Ser‐Lys‐Leu (LSKL) was applied to Met‐5A cells treated with 4.25% d ‐glucose to determine its function in high glucose‐induced MMT. Consequently, a uremic dialysate injection rat model was set up to confirm the results in vivo. Results: Exposure of Met‐5A cells to TSP‐1 increased TGF‐β1 secretion, expression and bioactivity, triggered Smad3 phosphorylation, upregulated the expression of mesenchymal molecules including fibronectin, collagen type III, α‐smooth muscle actin, Snail, and decreased calretinin expression. The effect was partially attenuated by TGF‐β1 neutralizing antibody. TSP‐1 expression in Met‐5A cells was increased by 4.25% d ‐glucose, followed by increased secretion and bioactivity of TGF‐β1, the onset of Smad3 phosphorylation and induction of MMT. LSKL significantly attenuated high glucose‐mediated mesothelial cell MMT and ameliorated peritoneal fibrosis in uremic rats receiving dextrose dialysate injection. Conclusions: Taken together, these data demonstrated that TSP‐1 contributes to mesothelial cell MMT by activating TGF‐β1/Smad3 signaling pathway and blockade of TSP‐1 attenuates high glucose‐mediated mesothelial cell MMT and peritoneal fibrosis. Abstract : TSP‐1 contributes to mesothelial cell MMT and peritoneum fibrogenesis. Transforming growth factor‐β1/Smad3 signaling pathway is activated by TSP‐1. Blockade of TSP‐1 attenuates high glucose‐mediated mesothelial cell MMT and peritoneal fibrosis.