Abstract
Background: Peritoneal fibrosis, in which inflammation and apoptosis play crucial pathogenic roles, is a severe complication associated with the treatment of kidney failure with peritoneal dialysis (PD) using a glucose-based dialysate. Mesothelial cells (MCs) take part in the inflammatory processes by producing various cytokines and chemokines, such as monocyte chemoattractant protein 1 (MCP-1) and interleukin 8 (IL-8). The apoptosis of MCs induced by high glucose levels also contributes to complications of PD. High mobility group protein B1 (HMGB1) is an inflammatory factor that has repeatedly been proven to be related to the occurrence of peritoneal dysfunction.Aim: In this study, we aimed to explore the effect and underlying mechanism of endogenous HMGB1 in high-glucose-induced MC injury.Methods: The human peritoneal MC line, HMrSV5 was cultured in high-glucose medium and incubated with recombinant HMGB1. Cellular expression of HMGB1 was blocked using HMGB1 small interfering RNA (siRNA). Apoptosis and production of inflammatory factors as well as the potential intermediary signaling pathways were examined.Results: The major findings of these analyses were: (1) MCs secreted HMGB1 from the nucleus during exposure to high glucose levels; HMGB1 acted in an autocrine fashion on the MCs to promote the production of MCP-1 and IL-8; (2) HMGB1 had little effect on high-glucose-induced apoptosis of the MCs; and (3) HMGB1-mediated MCP-1 and IL-8 production depended on the activation of MAPK signaling pathways. In conclusion, endogenous HMGB1 plays an important role in the inflammatory reaction induced by high glucose on MCs via mitogen-activated protein kinase (MAPK) signaling pathways, but it seems to have little effect on high-glucose-induced apoptosis.
Highlights
Peritoneal dialysis (PD) is a successful renal replacement therapy for end-stage renal disease (ESRD) that effectively extends the lives of patients
After treating Mesothelial cells (MCs) with high concentrations of glucose for different periods, increased concentrations of monocyte chemoattractant protein 1 (MCP-1) and IL8 were found in the culture supernatant by Enzyme-linked immunosorbent assay (ELISA) (Figure 1), which is consistent with previous studies (Ha and Lee, 2000; Welten et al, 2003)
We subsequently investigated the effects of specific p38 mitogen-activated protein kinase (MAPK) inhibitor, SB203580, ERK inhibitor, U0126, and JNK inhibitor, SP600125, on Recombinant human HMGB1 (rHMGB1)-mediated MCP-1 and interleukin 8 (IL-8) induction
Summary
Peritoneal dialysis (PD) is a successful renal replacement therapy for end-stage renal disease (ESRD) that effectively extends the lives of patients. High glucose as a major component of peritoneal dialysates plays an important role in the structural and functional alteration of the peritoneum by inducing apoptosis, inflammation, and epithelialto-mesenchymal transition (EMT) of peritoneal mesothelium (Yu et al, 2009; Hung et al, 2014). Apoptosis of MCs is a key factor contributing to cell death and complications in PD (Hung et al, 2014). Peritoneal fibrosis, in which inflammation and apoptosis play crucial pathogenic roles, is a severe complication associated with the treatment of kidney failure with peritoneal dialysis (PD) using a glucose-based dialysate. Mesothelial cells (MCs) take part in the inflammatory processes by producing various cytokines and chemokines, such as monocyte chemoattractant protein 1 (MCP-1) and interleukin 8 (IL-8). High mobility group protein B1 (HMGB1) is an inflammatory factor that has repeatedly been proven to be related to the occurrence of peritoneal dysfunction
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