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Blockade of thrombospondin‐1 ameliorates high glucose‐induced peritoneal fibrosis through downregulation of TGF‐β1/Smad3 signaling pathway
Author(s) -
Jiang Na,
Zhang Zhen,
Shao Xinghua,
Jing Ran,
Wang Chunlin,
Fang Wei,
Mou Shan,
Ni Zhaohui
Publication year - 2020
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.28976
Subject(s) - mesothelial cell , thrombospondin 1 , fibrosis , downregulation and upregulation , transforming growth factor , epithelial–mesenchymal transition , fibronectin , in vivo , endocrinology , neutralizing antibody , medicine , cancer research , chemistry , immunology , cell , biology , antibody , pathology , biochemistry , microbiology and biotechnology , angiogenesis , gene
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.