Peritoneal fibrosis contributes to ultrafiltration failure in
peritoneal dialysis (PD) patients and thus restricts the wide application of PD in clinic. Recently we have demonstrated that
histone deacetylase 6 (HDAC6) is critically implicated in high
glucose peritoneal dialysis fluid (HG-PDF) induced
peritoneal fibrosis, however, the precise mechanisms of HDAC6 in
peritoneal fibrosis have not been elucidated. Here, we focused on the role and mechanisms of HDAC6 in
chlorhexidine gluconate (CG) induced
peritoneal fibrosis and discussed the mechanisms involved. We found
Tubastatin A (TA), a selective inhibitor of HDAC6, significantly prevented the progression of
peritoneal fibrosis, as characterized by reduction of epithelial-mesenchymal transition (EMT) and extracellular matrix (ECM)
protein deposition. Inhibition of HDAC6 remarkably suppressed the expression of matrix metalloproteinases-2 (MMP2) and MMP-9. Administration of TA also increased the expression of acetylation
Histone H3 and acetylation α-
tubulin. Moreover, our results revealed that blockade of HDAC6 inhibited alternatively M2 macrophages polarization by suppressing the activation of TGF-β/Smad3, PI3K/AKT, and STAT3, STAT6 pathways. To give a better understanding of the mechanisms, we further established two cell injured models in Raw264.7 cells by using
IL-4 and HG-PDF. Our in vitro experiments illustrated that both
IL-4 and HG-PDF could induce M2 macrophage polarization, as demonstrated by upregulation of CD163 and Arginase-1. Inhibition of HDAC6 by TA significantly abrogated M2 macrophage polarization dose-dependently by suppressing TGF-β/Smad,
IL4/STAT6, and PI3K/AKT signaling pathways. Collectively, our study revealed that blockade of HDAC6 by TA could suppress the progression of CG-induced
peritoneal fibrosis by blockade of M2 macrophage polarization. Thus, HDAC6 may be a promising target in
peritoneal fibrosis treatment.