Abstract
BackgroundProgressive fibrous thickening of the peritoneal membrane is a complication of long-term peritoneal dialysis (PD). TGF-β/Smad pathway activation, inflammation, and neoangiogenesis play important roles in peritoneal membrane (PM) changes induced by PD. Recently, histone deacetilase inhibitors (HDACi) have shown anti-fibrotic and anti-inflammatory effects in different experimental models. These drugs prevent deacetylation of histones causing a loosen chromatin, which in turn induce the expression of some anti-fibrotic genes. In addition, acetylation may increase the activity of proteins involved in tissue fibrosis, such as Smad7. Here, we explored the effect of valproic acid (VPA), an HDACi, on the development of peritoneal fibrosis (PF) in rats.MethodsPF was induced by daily intraperitoneal injections of 0.1% chlorhexidine gluconate (CG) for 15 consecutive days. Male Wistar rats (250–300 g) were divided into 3 groups: CONTROL, control rats receiving only vehicle; PF, peritoneal fibrosis induced in rats; PF+VPA, rats with PF treated with VPA (300 mg/kg/day by gavage). PF was assessed by Masson’s trichrome staining. Inflammation and fibrosis-associated factors were assessed by immunohistochemistry, immunofluorescence, multiplex analysis, and qPCR.ResultsTreatment with VPA significantly reduced PM thickness and the expression of myofibroblasts, besides preventing loss of ultrafiltration capacity of the PM. The upregulation of profibrotic factors (TGF-β, fibronectin, and Smad3) in the PF group was significantly ameliorated by VPA. VPA modulated the TGF/Smad pathway, inhibiting phosphorylated Smad3 expression and inducing an increased Smad7 expression in the FP+VPA group. The neoangiogenesis and the expression of proinflammatory cytokines (TNF-α, IL-1β, MCP-1) observed in the PF group was significantly reduced by VPA.ConclusionsOur results indicate that VPA suppressed experimental PF through modulation of the TGF-β/Smad pathway. Interestingly, VPA treatment induced a higher expression of antifibrotic factors, such as Smad7. These results suggest that VPA may represent a potential strategy for treating long term PD complications.
Highlights
Despite the predominance of hemodialysis as renal replacement therapy, the best method of dialysis for patients with end-stage renal disease has not been established
Male Wistar rats (250–300 g) were divided into 3 groups: CONTROL, control rats receiving only vehicle; PF, peritoneal fibrosis induced in rats; PF+valproic acid (VPA), rats with PF treated with VPA (300 mg/kg/day by gavage)
The neoangiogenesis and the expression of proinflammatory cytokines (TNF-α, IL-1β, monocyte chemoattractant protein-1 (MCP-1)) observed in the PF group was significantly reduced by VPA
Summary
Despite the predominance of hemodialysis as renal replacement therapy, the best method of dialysis for patients with end-stage renal disease has not been established. The pivotal role of the TGF-β/Smad signaling pathway in the pathogenesis of peritoneal changes induced by PD have been demonstrated [7,8,9,10]. Inhibiting TGF-β or enhancing Smad expression likely represents an effective therapy for peritoneal fibrosis. TGF-β/Smad pathway activation, inflammation, and neoangiogenesis play important roles in peritoneal membrane (PM) changes induced by PD. Histone deacetilase inhibitors (HDACi) have shown anti-fibrotic and anti-inflammatory effects in different experimental models. These drugs prevent deacetylation of histones causing a loosen chromatin, which in turn induce the expression of some anti-fibrotic genes. We explored the effect of valproic acid (VPA), an HDACi, on the development of peritoneal fibrosis (PF) in rats
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