Abstract
IL-6 is a vital inflammatory factor in the peritoneal cavity of patients undergoing peritoneal dialysis (PD). The present study examined the effect of IL-6 trans-signaling on structural alterations of the peritoneal membrane. We investigated whether the epithelial-to-mesenchymal transition (EMT) process of human peritoneal mesothelial cells (HPMCs) and the production of proangiogenic factors were controlled by IL-6 trans-signaling. Its role in the peritoneal alterations was detected in a mouse model. The morphology of HPMCs and levels of cytokines in PD effluent were also explored. Stimulation of HPMCs with the IL-6 and soluble IL-6 receptor complex (IL-6/S) promoted the EMT process of HPMCs depending on the STAT3 pathway. In a coculture system of HPMCs and human umbilical vein endothelial cells, IL-6/S mediated the production of VEGF and angiopoietins so as to downregulate the expression of endothelial junction molecules and finally affect vascular permeability. Daily intraperitoneal injection of high glucose-based dialysis fluid induced peritoneal fibrosis, angiogenesis, and macrophage infiltration in a mouse model, accompanied by phosphorylation of STAT3. Blockade of IL-6 trans-signaling prevented these peritoneum alterations. The fibroblast-like appearance of HPMCs ex vivo was upregulated in patients undergoing prevalent PD accompanied by increasing levels of IL-6, VEGF, and angiopoietin-2 in the PD effluent. Taken together, these findings identified a critical link between IL-6 trans-signaling and structural alterations of the peritoneal membrane, and it might be a potential target for the treatment of patients undergoing PD who have developed peritoneal alterations.
Highlights
Peritoneal dialysis (PD) has been a well-established therapeutic modality for patients with end-stage renal disease (ESRD)
To explore the significance of IL-6 trans-signaling in peritoneal fibrosis, we studied the phenotypic transition of human peritoneal mesothelial cells (HPMCs) incubated with IL-6 combined with sIL-6R (IL-6/S)
To explore the mechanism by which IL-6 trans-signaling activation contributed to the epithelial-to-mesenchymal transition (EMT) process of HPMCs, we examined the effect of IL-6/S on the activation of Smad3, a key signaling molecule of the transforming growth factor (TGF)-1 signaling pathway in HPMCs
Summary
Peritoneal dialysis (PD) has been a well-established therapeutic modality for patients with end-stage renal disease (ESRD). Its efficacy depends on both the structural and functional integrity of the peritoneal membrane. Typical features of structural alterations include loss of mesothelial cells, abnormal proliferation of ␣-smooth muscle actin (␣SMA)-positive fibroblasts, and thickening of the submesothelial area with an accumulation of collagen [20, 39, 40]. Peritoneal injury leads to peritoneal sclerosis, a serious complication of PD. In parallel with these alterations, the peritoneal membrane undergoes typical functional changes including an increased peritoneal small-solute transport rate (PSTR), leading to impaired ultrafiltration and discontinuation of treatment [5]
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