RESUMO
Preclinical studies suggest that Gremlin participates in renal damage and could be a potential therapeutic target for human chronic kidney diseases. Inflammation is a common characteristic of progressive renal disease, and therefore novel anti-inflammatory therapeutic targets should be investigated. The Notch signaling pathway is involved in kidney development and is activated in human chronic kidney disease, but whether Gremlin regulates the Notch pathway has not been investigated. In cultured tubular cells, Gremlin up-regulated gene expression of several Notch pathway components, increased the production of the canonical ligand Jagged-1, and caused the nuclear translocation of active Notch-1 (N1ICD). In vivo administration of Gremlin into murine kidneys elicited Jagged-1 production, increased N1ICD nuclear levels, and up-regulated the gene expression of the Notch effectors hes-1 and hey-1 All these data clearly demonstrate that Gremlin activates the Notch pathway in the kidney. Notch inhibition using the γ-secretase inhibitor DAPT impaired renal inflammatory cell infiltration and proinflammatory cytokines overexpression in Gremlin-injected mice and in experimental models of renal injury. Moreover, Notch inhibition blocked Gremlin-induced activation of the canonical and noncanonical nuclear factor-κB (NF-κB) pathway, identifying an important mechanism involved in the anti-inflammatory actions of Notch inhibition. In conclusion, Gremlin activates the Notch pathway in the kidney and this is linked to NF-κB-mediated inflammation, supporting the hypothesis that Notch inhibition could be a potential anti-inflammatory strategy for renal diseases.
Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Nefrite/fisiopatologia , Receptores Notch/efeitos dos fármacos , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Animais , Células Cultivadas , Diaminas/uso terapêutico , Humanos , Mediadores da Inflamação/metabolismo , Proteína Jagged-1/biossíntese , Túbulos Renais Proximais/citologia , Túbulos Renais Proximais/efeitos dos fármacos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Nefrite/tratamento farmacológico , Receptores Notch/antagonistas & inibidores , Receptores Notch/genética , Receptores Notch/fisiologia , Proteínas Recombinantes/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Tiazóis/uso terapêutico , Regulação para Cima/efeitos dos fármacos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
The association between breast cancer initiation and prolonged exposure to estrogen suggests that this hormone may also have an etiologic role in such a process. On the other hand, many studies have found an association between human cancer and exposure to agricultural pesticides such as parathion, an organophosphorous pesticide used in agriculture to control mosquito plagues. However, the key factors behind the initiation of breast cancer remain to be elucidated. The aim of this study was to determine the effect of 17beta estradiol (estrogen) and parathion on protein expression in cell transformation of human breast epithelial cells in vitro. Estrogen and parathion alone and in combination induced malignant transformation of an immortalized human breast epithelial cell line, MCF-I0F, as indicated by anchorage independency and invasive capabilities. The results indicate that a combination of estrogen and parathion increased the expression of related cell adhesion proteins such as Dvl, Notch, CD146 and beta catenin. In conclusion, it can be suggested that pesticides affect human breast cell adhesion changes indicative of transformation.