Histone deacetylase 6 inhibition counteracts the epithelial-mesenchymal transition of peritoneal mesothelial cells and prevents peritoneal fibrosis

作者：Xu, Liuqing; Liu, Na^*; Gu, Hongwei; Wang, Hongrui; Shi, Yingfeng; Ma, Xiaoyan; Ma, Shuchen; Ni, Jun; Tao, Min; Qiu, Andong; Zhuang, Shougang^*

来源：Oncotarget, 2017, 8(51): 88730-88750.

DOI：10.18632/oncotarget.20982

• peritoneal fibrosis
• HDAC6
• TGF-beta signaling pathway
• inflammation
• vascular endothelial growth factor

The role of histone deacetylase 6 (HDAC6) in peritoneal fibrosis remains unknown. In this study, we examined the effect of HDAC6 inhibition on the epithelial-mesenchymal transition (EMT) of peritoneal mesothelial cells and development of peritoneal fibrosis. Treatment with tubastatin A, a highly selective HDAC6 inhibitor, or silencing of HDAC6 with siRNA inhibited transforming growth factor beta 1-induced EMT, as evidenced by decreased expression of alpha-smooth muscle actin, collagen I and preserved expression of E-cadherin in cultured human peritoneal mesothelial cells. In a mouse model of peritoneal fibrosis induced by high glucose dialysate, administration of TA prevented thickening of the submesothelial region and decreased expression of collagen I and alpha-SMA. Mechanistically, tubastatin A treatment inhibited expression of TGF-beta 1 and phosphorylation of Smad-3, epidermal growth factor receptor, STAT3, and NF-kappa Bp65. HDAC6 inhibition also suppressed production of multiple inflammatory cytokines/chemokines and reduced the infiltration of macrophages to the injured peritoneum. Moreover, tubastatin A was effective in inhibiting peritoneal increase of CD31(+) blood vessels and expression of vascular endothelial growth factor in the injured peritoneum. Collectively, these results suggest that HDAC6 inhibition can attenuate peritoneal fibrosis by inhibiting multiple pro-fibrotic signaling pathways, EMT, inflammation and blood vessel formation.

• 出版日期2017-10-24
• 单位同济大学