Abstract
BackgroundHigh glucose concentrations influence the functional and structural development of the peritoneal membrane. We previously reported that the oral administration of astaxanthin (AST) suppressed peritoneal fibrosis (PF) as well as inhibited oxidative stress, inflammation, and epithelial–mesenchymal transition (EMT) of peritoneal mesothelial cells (PMCs) in a chlorhexidine-induced PF rat model. This suggests that oxidative stress induction of EMT is a key event during peritoneal damage. The present study evaluated the therapeutic effect of AST in suppressing EMT, in response to glucose-induced oxidative stress.MethodsTemperature-sensitive mesothelial cells (TSMCs) were cultured in the presence or absence of AST and then treated with 140 mM glucose for 3 or 12 hours. Expression levels of TNF-α, TGF-β, and VEGF were determined at the mRNA and protein levels, and nuclear factor kappa B (NF-κB) activity was evaluated. We measured NO2−/NO3− concentrations in cellular supernatants and determined 8-hydroxy-2′-deoxyguanosine (8-OHdG) levels in mitochondrial and nuclear DNA. The expressions of E-cadherin and alpha-smooth muscle actin (α-SMA) were evaluated by double immunofluorescence and protein levels.ResultsHigh glucose concentrations induced overproduction of reactive oxidative species (ROS), increasing 8-OHdG mitochondrial DNA and cytokine levels. The NF-κB pathway was activated in response to high glucose concentrations, whereas de novo α-SMA expression was observed with decreased E-cadherin expression. AST treatment attenuated ROS production, inflammatory cytokine production, NF-κB activation, and EMT.ConclusionThe findings of the present study indicate that AST may have an anti-EMT effect due to anti-oxidative and anti-inflammatory activities by scavenging glucose-induced ROS from mitochondria in PMCs. AST may be an efficacious treatment for PF.
Highlights
Peritoneal dialysis (PD) is an attractive treatment option for patients with end-stage kidney disease
We previously reported that the oral administration of astaxanthin (AST) suppressed peritoneal fibrosis (PF) as well as inhibited oxidative stress, inflammation, and epithelial–mesenchymal transition (EMT) of peritoneal mesothelial cells (PMCs) in a chlorhexidine-induced PF rat model
The NF-κB pathway was activated in response to high glucose concentrations, whereas de novo α-SMA expression was observed with decreased E-cadherin expression
Summary
Peritoneal dialysis (PD) is an attractive treatment option for patients with end-stage kidney disease. Over the long term, PD patients develop functional and morphological alterations in the peritoneal membrane [1], limiting treatment benefits. The cumulative exposure of the peritoneum to unphysiologically high concentrations of glucose induces morphological changes in the peritoneum, including mesothelial cell loss, vasculopathy, and fibrotic thickening of the peritoneal interstitium [2,3,4]. Previous reports indicate that glucose degradation products and advanced glycation end products induce functional and morphological peritoneal alterations [6], with alterations observed in some patients during early phase PD therapy. Ciszewics et al reported that high glucose concentrations accelerate aging in human peritoneal mesothelial cells (PMCs) [7]. The present study evaluated the therapeutic effect and underlying mechanisms of AST in suppressing EMT in response to glucose-induced oxidative stress
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