Abstract
Aims: Influenced by microenvironment, human peritoneal mesothelial cells (HPMCs) acquired fibrotic phenotype, which was identified as the protagonist for peritoneal fibrosis. In this study, we examined the role of histone deacetylase 6 (HDAC6) for interleukin-6 (IL-6) induced epithelial-mesenchymal transition (EMT), proliferation, and migration of HPMCs.Methods: The role of HDAC6 in IL-6-elicited EMT of HPMCs was tested by morphological observation of light microscope, immunoblotting, and immune-fluorescence assay; and the function of HDAC6 in proliferation and migration of HPMCs was examined by CCK-8 assay, wound healing experiment, and immunoblotting.Results: IL-6 stimulation significantly increased the expression of HDAC6. Treatment with tubastatin A (TA), a highly selective HDAC6 inhibitor, or silencing of HDAC6 with siRNA decreased the expression of HDAC6. Moreover, TA or HDAC6 siRNA suppressed IL-6-induced EMT, as evidenced by decreased expressions of α-SMA, Fibronectin, and collagen I and the preserved expression of E-cadherin in cultured HPMCs. Mechanistically, HDAC6 inhibition suppressed the expression of transforming growth factor β (TGFβ) receptor I (TGFβRI), phosphorylation of Smad3, secretion of connective tissue growth factor (CTGF), and transcription factor Snail. On the other hand, the pharmacological inhibition or genetic target of HDAC6 suppressed HPMCs proliferation, as evidenced by the decreased optical density of CCK-8 and the expressions of PCNA and Cyclin E. The migratory rate of HPMCs also decreased. Mechanistically, HDAC6 inhibition blocked the activation of JAK2 and STAT3.Conclusion: Our study illustrated that IL-6-induced HDAC6 not only regulated IL-6 itself downstream JAK2/STAT3 signaling but also co-activated the TGF-β/Smad3 signaling, leading to the change of the phenotype and mobility of HPMCs. HDAC6 could be a potential therapeutic target for the prevention and treatment of peritoneal fibrosis.
Highlights
Peritoneal dialysis (PD) is an effective and home-based renal replacement therapy for end-stage renal disease (ESRD) patients (Li et al, 2017)
We aimed to investigate the mechanism by which IL-6 regulated the peritoneal fibrosis
We found that the exposure of human peritoneal mesothelial cells (HPMCs) to IL-6 at 100 ng/ml changed the cell morphology into fusiform or spindle shape (Figure 1A) and increased the expression level of Histone deacetylase 6 (HDAC6) and decreased the expression of Acetyl Histone H3 and Acetyl α-Tubulin in the cultured HPMCs (Figures 1B–D)
Summary
Peritoneal dialysis (PD) is an effective and home-based renal replacement therapy for end-stage renal disease (ESRD) patients (Li et al, 2017). Peritoneal mesothelial cells under phenotypic transformation often acquire the capacity of proliferation and invasiveness and secrete more cell cycle associated proteins, such as proliferating cell nuclear antigen (PCNA) and Cyclin E (He et al, 2015). This process is triggered via the activation of the canonical transforming growth factor-β (TGF-β) pathway (Zhou Q. et al, 2016). The noncanonical inflammatory cytokines-elicited EMT arouses the attention of researchers
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