RESUMEN
BACKGROUND: Progressive fibrous thickening of the peritoneal membrane is a complication of long-term peritoneal dialysis (PD). TGF-ß/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-ß, 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-1ß, 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-ß/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.
Asunto(s)
Fibrosis Peritoneal/inducido químicamente , Fibrosis Peritoneal/tratamiento farmacológico , Ácido Valproico/uso terapéutico , Animales , Transporte Biológico/efectos de los fármacos , Biomarcadores/metabolismo , Peso Corporal/efectos de los fármacos , Proteína Morfogenética Ósea 7/genética , Proteína Morfogenética Ósea 7/metabolismo , Proteínas de Unión al Calcio/genética , Proteínas de Unión al Calcio/metabolismo , Capilares/metabolismo , Recuento de Células , Citocinas/metabolismo , Fibronectinas/genética , Fibronectinas/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Inflamación/patología , Mediadores de Inflamación , Masculino , Miofibroblastos/efectos de los fármacos , Miofibroblastos/metabolismo , Miofibroblastos/patología , Neovascularización Fisiológica , Fibrosis Peritoneal/genética , Fibrosis Peritoneal/patología , Peritoneo/efectos de los fármacos , Peritoneo/metabolismo , Peritoneo/patología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Proteínas Smad/metabolismo , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismo , Resultado del Tratamiento , Ácido Valproico/farmacología , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
INTRODUCTION:: We evaluated the associations between interleukin-10 (IL-10) gene polymorphisms -G1082A/-C819T/-C592A and periportal fibrosis regression after specific treatment for schistosomiasis. METHODS:: This retrospective cohort study involved 125 Brazilian patients infected with Schistosomiasis mansoni, who were followed up for 2 years after specific treatment to estimate the probability of periportal fibrosis regression. RESULTS:: There was no evidence of associations between IL-10 polymorphisms and periportal fibrosis regression after treatment. CONCLUSIONS:: There was no evidence of associations between gene promoter polymorphisms of IL-10 and the regression of periportal fibrosis in this Brazilian population.
Asunto(s)
Interleucina-10/genética , Fibrosis Peritoneal/genética , Esquistosomiasis mansoni/complicaciones , Humanos , Fibrosis Peritoneal/tratamiento farmacológico , Fibrosis Peritoneal/parasitología , Polimorfismo Genético , Estudios Retrospectivos , Índice de Severidad de la EnfermedadRESUMEN
Abstract INTRODUCTION: We evaluated the associations between interleukin-10 (IL-10) gene polymorphisms -G1082A/-C819T/-C592A and periportal fibrosis regression after specific treatment for schistosomiasis. METHODS: This retrospective cohort study involved 125 Brazilian patients infected with Schistosomiasis mansoni, who were followed up for 2 years after specific treatment to estimate the probability of periportal fibrosis regression. RESULTS: There was no evidence of associations between IL-10 polymorphisms and periportal fibrosis regression after treatment. CONCLUSIONS: There was no evidence of associations between gene promoter polymorphisms of IL-10 and the regression of periportal fibrosis in this Brazilian population.
Asunto(s)
Humanos , Esquistosomiasis mansoni/complicaciones , Interleucina-10/genética , Fibrosis Peritoneal/genética , Polimorfismo Genético , Índice de Severidad de la Enfermedad , Estudios Retrospectivos , Fibrosis Peritoneal/parasitología , Fibrosis Peritoneal/tratamiento farmacológicoRESUMEN
Interleukin 10 (IL-10) is an important anti-inflammatory cytokine that modulates severe periportal fibrosis (PPF). We hypothesized that genetic polymorphisms (-G1082A/-C819T/-C592A) of the IL-10 gene and classic factors (age, sex, alcohol, exposure, and specific treatment) are associated with the severity of PPF and that these polymorphisms influence IL-10 expression. In this cross-sectional study, we genotyped these polymorphisms within the IL-10 gene in 203 Brazilian subjects infected with Schistosoma mansoni, with different patterns of PPF. There was an association of protection between the ages of 41 and 60 years and advanced standard PPF. The -1082AA genotype was significantly associated with severity in PPF when compared with the -1082GG genotype. Similarly, when analyzed together, both the -1082GA+AA genotypes were significantly associated. The ACC and GTA haplotypes indicated a protective effect against PPF, while the ATA haplotype was significantly associated with PPF severity when compared with the GCC haplotype. There was no significant difference between average levels of IL-10 between clinical groups, and there was no association between average serum levels of IL-10 and (-G1082A) IL-10 polymorphism. Our results suggest that (-G1082A) IL-10 polymorphism and putative haplotypes are associated with PPF severity in the Brazilian population.