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

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

doi:10.18632/oncotarget.20982

Liuqing Xu, Hongwei Gu + Show 9 more

Open Access

https://doi.org/10.18632/oncotarget.20982

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Abstract

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.

Highlights

Peritoneal dialysis (PD) is an effective alternative form of renal replacement therapy in patients with end-stage renal disease (ESRD) [1]
Since histone H3 is a nuclear protein and α-tubulin is located in the cytosol, these data suggest that histone deacetylase 6 (HDAC6) acts in both nucleus and cytosol to regulate epithelial– mesenchymal transition (EMT) in peritoneal mesothelial cells
We demonstrated that inhibition of HDAC6 with tubastatin A (TA) or silencing with siRNA inhibits EMT in cultured human peritoneal mesothelial cells and attenuates activation of fibroblasts, deposition of extracellular matrix (ECM), induction of inflammatory responses, and angiogenesis in a mouse model of peritoneal fibrosis induced by chronic exposure to high glucose dialysate

Summary

Introduction

Peritoneal dialysis (PD) is an effective alternative form of renal replacement therapy in patients with end-stage renal disease (ESRD) [1]. Long-term exposure to a diversity of unfavorable factors including bio-incompatible PD solution, uremia, peritonitis and basic chronic kidney diseases [2], results in structural changes of the peritoneal membrane These changes include loss of mesothelial cells, occurrence of epithelial-mesenchymal transition (EMT), thickening of the submesothelial region and induction of angiogenesis. Whereas Lua et al demonstrated that approximately 17% of myofibroblasts are derived from mesothelial cells during peritoneal fibrosis [7], Chen et al revealed that submesothelial fibroblasts are the major source of myofibroblast precursors [8] Both studies still support the importance of mesothelial cells in the development of peritoneal fibrosis since injured mesothelial cells acquire a capability to produce multiple cytokines/growth factors that stimulate resident fibroblast activation and proliferation, thereby producing more ECM proteins and supporting the development of peritoneal fibrosis [7,8,9]

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