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.