Please use this identifier to cite or link to this item: https://observatorio.fm.usp.br/handle/OPI/21790
Title: Anti-fibrotic effects of valproic acid in experimental peritoneal fibrosis
Authors: COSTALONGA, Elerson C.FREITAS, Luiza J. deARAGONE, Deise da S. P.SILVA, Filipe M. O.NORONHA, Irene L.
Citation: PLOS ONE, v.12, n.9, article ID e0184302, 17p, 2017
Abstract: Background Progressive fibrous thickening of the peritoneal membrane is a complication of long-term peritoneal dialysis (PD). TGF-beta/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. Methods PF 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. Results Treatment 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-beta, 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-alpha, IL-1 beta, MCP-1) observed in the PF group was significantly reduced by VPA. Conclusions Our results indicate that VPA suppressed experimental PF through modulation of the TGF-beta/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.
Appears in Collections:

Artigos e Materiais de Revistas Científicas - FM/MCM
Departamento de Clínica Médica - FM/MCM

Artigos e Materiais de Revistas Científicas - HC/ICESP
Instituto do Câncer do Estado de São Paulo - HC/ICESP

Artigos e Materiais de Revistas Científicas - HC/ICHC
Instituto Central - HC/ICHC

Artigos e Materiais de Revistas Científicas - LIM/29
LIM/29 - Laboratório de Nefrologia Celular, Genética e Molecular

Artigos e Materiais de Revistas Científicas - ODS/03
ODS/03 - Saúde e bem-estar


Files in This Item:
File Description SizeFormat 
art_COSTALONGA_Antifibrotic_effects_of_valproic_acid_in_experimental_peritoneal_2017.PDFpublishedVersion (English)9.85 MBAdobe PDFThumbnail
View/Open

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.