EZH2 promotes angiogenesis in peritoneal dialysis by epigenetically activating SP4 expression in the IL-6/sIL-6R signalling pathway

Abstract

Background: Interleukin-6 (IL-6)/soluble IL-6 receptor (sIL-6R) promotes peritoneal angiogenesis by stimulating SP4-mediated vascular endothelial growth factor (VEGF) production in peritoneal dialysis (PD). Moreover, histone methyltransferase enhancer of zeste homologue 2 (EZH2) is involved in IL-6/sIL-6R signalling via the acceleration of vascular endothelial growth factor (VEGF)-induced angiogenesis. However, the molecular mechanism underlying how EZH2 epigenetically activates VFGF expression in IL-6/sIL-6R signalling during PD is still unclear. Methods and Results: In this study, we measured the expression of EZH2, DNMT3B and SP4 in human peritoneal mesothelial cells (HPMCs) treated with IL-6/sIL-6R stimulation and/or EZH2 overexpression, silencing or inhibition. Methylation of the CpG site in the SP4 promoter region and VEGF production were measured under these treatments in HPMCs. Moreover, tube formation in human umbilical vein endothelial cells (HUVECs) was detected following treatment with conditioned media from these stimulated HPMCs. The 5/6 nephrectomy (5/6Nx) rat model was established, and the rats were injected with peritoneal dialysate. EZH2, DNMT3B and SP4 expression and microvessels were analysed in 5/6Nx + PD rats treated with IL-6/sIL-6R and EZH2 overexpression. The results showed that IL-6/sIL-6R and EZH2 overexpression enhanced the expression of EZH2, DNMT3B and SP4, but EZH2 silencing/inhibition reduced these expression levels. The results for VEGF production and tube formation in vitro followed the same trend. IL-6/sIL-6R and EZH2 overexpression increased the methylation percentage of the -170 bp CpG site in the SP4 promoter region in HPMCs. Moreover, IL-6/sIL-6R and EZH2 overexpression stimulated EZH2, DNMT3B and SP4 expression and promoted angiogenesis in 5/6Nx + PD rats. Conclusions: Thus, this study indicated that EZH2 is involved in IL-6/sIL-6R signalling and epigenetically regulates SP4 expression, thereby stimulating VEGF production and angiogenesis in PD. Targeting EZH2 is expected to be a novel therapeutic approach for end-stage renal disease (ESRD) patients with PD treatment.

Integrative bioinformatics analysis of miRNA and mRNA expression profiles and identification of associated miRNA-mRNA network in intracranial aneurysms

“…In a recent study, SP1 was confirmed to mediate the impact of miR-335-5p on the phenotypic switching of VSMCs in AAD, exhibiting a pro-apoptotic influence by repressing the expression of p21WAF1/Cip1 at the transcriptional, mRNA, and protein levels [ 50 , 51 ]. Additionally, SP1 and SP4 have been recognized as key TFs involved in the regulation of vascular endothelial growth factor (VEGF) production by binding to specific sites in the VEGF promoter [ 52 , 53 ]. KLF7's involvement in various cardiovascular diseases is well-documented.…”

Pro‐inflammatory cytokine IL‐6 regulates LMO4 expression in psoriatic keratinocytes via AKT/STAT3 pathway

“…[20][21][22][23][24][25] Among these cytokines, IL-6 is a pleiotropic cytokine involved in epithelial and immune cell angiogenesis, proliferation, and differentiation. [26][27][28][29] Owing to its excessive activation and dysregulation of receptor signaling in T cells, IL-6 is involved in the pathogenesis of psoriasis. [30][31][32][33] IL-6 contributes to the differentiation and maintenance of T helper (Th) 17 cell development and function and inhibits regulatory T cell (Treg) differentiation.…”

“…The upregulation of other cytokines, such as IL‐6, IL‐12, IL‐22, IL‐29, IL‐36, IL‐1 β, and tumor necrosis factor‐α, is also involved in the pathogenesis of psoriasis 20–25 . Among these cytokines, IL‐6 is a pleiotropic cytokine involved in epithelial and immune cell angiogenesis, proliferation, and differentiation 26–29 . Owing to its excessive activation and dysregulation of receptor signaling in T cells, IL‐6 is involved in the pathogenesis of psoriasis 30–33 .…”