Use of inhibitor of histone deacetylase hdac6 in preparation of medicine for preventing and treating peritoneal fibrosis after peritoneal dialysis
A deacetylase and peritoneal dialysis technology, which is applied in the field of pharmaceuticals to achieve the effects of improving peritoneal function, reducing peritoneal pathological changes and making significant technological progress
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Embodiment 1
[0028] Example 1 Materials and methods
[0029] 1) p-STAT3, STAT3, p-Smad3, Smad3, p-NF-κBp65, NF-κBp65, p-EGFR, EGFR, Histone H3, Acetyl-Histone H3 and HDAC6 antibodies were purchased from Cell Signaling Technology Company. Collagen I (A2), TGF-β, CD68, EGFR, VEGF, CD31 and GAPDH antibodies were purchased from Santa Cruz Company. TNF-α, IL-1β, MCP-1, IL-6 and TGF-β1 (ELISA) kits were purchased from Roche Life Science. Tubastatin A was purchased from Selleckchem. α-SMA antibody and other reagents were purchased from Sigma.
[0030] Peritoneal Fibrosis Models and Treatment Groups
[0031] A mouse model of peritoneal fibrosis was established according to the method reported in the literature. The mice were randomly divided into four groups, and the blank control group was intraperitoneally injected with 0.9% normal saline 3ml / mouse, once a day for 4 consecutive weeks. TA group was intraperitoneally injected with TA 70mg / kg, once a day, for four consecutive weeks. The model...
Embodiment 2
[0040] Example 2 TA inhibits TGF-β-induced peritoneal mesothelial cell transdifferentiation (EMT)
[0041] It has been reported that HDAC6 activation occurs during renal interstitial fibrosis. However, the role of HDAC6 in peritoneal fibrosis remains unclear. The first step is to understand whether HDAC6 is involved in the process of peritoneal fibrosis. We study the effect of TA on TGF-β-induced peritoneal mesothelial cell fibrosis in peritoneal mesothelial cells. Two EMT biomarkers, α-SMA and collagen I, were significantly increased in TGF-β-treated cells, while the expression of HDAC6 was also increased, and the expression of acetyl-histone H3 was decreased. On the contrary, in the TA intervention group, the increase of α-SMA, collagen I and HDAC6 induced by TGF-β was inhibited, and at the same time, the expression of acetyl-histone H3 was up-regulated, and reached the maximum at the concentration of 20 μM ( figure 1 A-F). Because histone H3 is a nuclear protein, our stu...
Embodiment 3
[0042] Example 3 HDAC6 siRNA inhibits transdifferentiation of peritoneal mesothelial cells
[0043] To demonstrate the inhibitory effect of TA on epithelial-mesenchymal cell transdifferentiation, we specifically knocked down HDAC6 in peritoneal mesenchymal cells using HDAC6 siRNA. figure 2 A-D show that reducing the expression of HDAC6 by specific siRNA can also reduce the α-SMA and collagen I induced by TGF-β. In addition, down-regulation of HDAC6 level can also increase the expression of acetyl histone H3 without changing the total histone H3 level ( figure 2 E and F). These results suggest that HDAC6 plays an important role in mediating epithelial-mesenchymal transdifferentiation of peritoneal mesothelial cells.
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