Histone deacetylase 8 inhibition prevents the progression of peritoneal fibrosis by counteracting the epithelial-mesenchymal transition and blockade of M2 macrophage polarization

Abstract

BackgroundPeritoneal dialysis (PD) is an effective replacement therapy for end-stage renal disease patients. However, long-term exposure to peritoneal dialysate will lead to the development of peritoneal fibrosis. Epigenetics has been shown to play an important role in peritoneal fibrosis, but the role of histone deacetylases 8 (HDAC8) in peritoneal fibrosis have not been elucidated. In this research, we focused on the role and mechanisms of HDAC8 in peritoneal fibrosis and discussed the mechanisms involved.MethodsWe examined the expression of HDAC8 in the peritoneum and dialysis effluent of continuous PD patients. Then we assessed the role and mechanism of HDAC8 in peritoneal fibrosis progression in mouse model of peritoneal fibrosis induced by high glucose peritoneal dialysis fluid by using PCI-34051. In vitro, TGF-β1 or IL-4 were used to stimulate human peritoneal mesothelial cells (HPMCs) or RAW264.7 cells to establish two cell injury models to further explore the role and mechanism of HDAC8 in epithelial-mesenchymal transition (EMT) and macrophage polarization.ResultsWe found that HDAC8 expressed highly in the peritoneum from patients with PD-related peritonitis. We further revealed that the level of HDAC8 in the dialysate increased over time, and HDAC8 was positively correlated with TGF-β1 and vascular endothelial growth factor (VEGF), and negatively correlated with cancer antigen 125. In mouse model of peritoneal fibrosis induced by high glucose dialysate, administration of PCI-34051 (a selective HDAC8 inhibitor) significantly prevented the progression of peritoneal fibrosis. Treatment with PCI-34051 blocked the phosphorylation of epidermal growth factor receptor (EGFR) and the activation of its downstream signaling pathways ERK1/2 and STAT3/HIF-1α. Inhibition of HDAC8 also reduced apoptosis. In vitro, HDAC8 silencing with PCI-34051 or siRNA inhibited TGF-β1-induced EMT and apoptosis in HPMCs. In addition, continuous high glucose dialysate or IL-4 stimulation induced M2 macrophage polarization. Blockade of HDAC8 reduced M2 macrophage polarization by inhibiting the activation of STAT6 and PI3K/Akt signaling pathways. ConclusionsWe demonstrated that HDAC8 promoted the EMT of HPMCs via EGFR/ERK1/2/STAT3/HIF-1α, induced M2 macrophage polarization via STAT6 and PI3K/Akt signaling pathways, and ultimately accelerated the process of peritoneal fibrosis.

Type II Interleukin-4 Receptor Activation in Basal Breast Cancer Cells Promotes Tumor Progression via Metabolic and Epigenetic Modulation

“…However, using more targeted methods, we could identify IL4 target genes where histone acetylation was active. Other epigenetic modifications are known to be modulated by IL4 in immune cells, such as histone deacetylation [43,44], histone demethylation [45][46][47], and DNA demethylation [48]. In this study, we did not examine the contributions of these modifications; however, it is likely that they play a role.…”

Intercellular communication in peritoneal dialysis

“…Furthermore, histone deacetylase 8 (HDAC8) is a crucial enzyme for controlling the polarization of M2 macrophages via the STAT6 and PI3K/Akt signaling pathways. HDAC8 promotes EMT by inducing the phosphorylation of EGFR, which conversely, leads to the activation of its downstream fibrotic signaling pathways, including STAT3/HIF-1α and ERK1/2 ( Zhou et al, 2023 ).…”

Impacts of epigenetic reprogramming on innate immunity

“…For instance, HDAC10 is upregulated in macrophages and the upregulation promotes activation of mouse M2 macrophages [123] . Inhibiting HDAC6 and HDAC8 suppresses macrophage M2 polarization [124][125][126] . Moreover, inhibition of HDAC6 and HDAC3 substantially suppresses LPS-induced macrophage M1 polarization and reduces pro-inflammatory https://doi.org/10.1017/anr.2024.9 Published online by Cambridge University Press cytokine production [127] .…”