Histone deacetylase 6 inhibition counteracts the epithelial–mesenchymal transition of peritoneal mesothelial cells and prevents peritoneal fibrosis
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Liuqing Xu1,*, Na Liu1,*, Hongwei Gu1,*, Hongrui Wang1,*, Yingfeng Shi1, Xiaoyan Ma1, Shuchen Ma1, Jun Ni1, Min Tao1, Andong Qiu2 and Shougang Zhuang1,3
1Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
2School of Life Sciences and Technology, Advanced Institute of Translational Medicine, Tongji University, Shanghai, China
3Department of Medicine, Rhode Island Hospital and Brown University School of Medicine, Providence, RI, USA
*These authors have contributed equally to this work
Na Liu, email: firstname.lastname@example.org
Shougang Zhuang, email: email@example.com
Keywords: peritoneal fibrosis, HDAC6, TGF-β signaling pathway, inflammation, vascular endothelial growth factor
Received: July 14, 2017 Accepted: August 27, 2017 Published: September 18, 2017
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 β1-induced EMT, as evidenced by decreased expression of α-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 α-SMA. Mechanistically, tubastatin A treatment inhibited expression of TGF-β1 and phosphorylation of Smad-3, epidermal growth factor receptor, STAT3, and NF-κBp65. 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.
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