Triptolide decreases podocytes permeability by regulating TET2-mediated hydroxymethylation of ZO-1.
Exp Biol Med (Maywood)
; 249: 10051, 2024.
Article
em En
| MEDLINE
| ID: mdl-38881848
ABSTRACT
Podocyte injury or dysfunction can lead to proteinuria and glomerulosclerosis. Zonula occludens 1 (ZO-1) is a tight junction protein which connects slit diaphragm (SD) proteins to the actin cytoskeleton. Previous studies have shown that the expression of ZO-1 is decreased in chronic kidney disease (CKD). Thus, elucidation of the regulation mechanism of ZO-1 has considerable clinical importance. Triptolide (TP) has been reported to exert a strong antiproteinuric effect by inhibiting podocyte epithelial mesenchymal transition (EMT) and inflammatory response. However, the underlying mechanisms are still unclear. We found that TP upregulates ZO-1 expression and increases the fluorescence intensity of ZO-1 in a puromycin aminonucleoside (PAN)-induced podocyte injury model. Permeablity assay showed TP decreases podocyte permeability in PAN-treated podocyte. TP also upregulates the DNA demethylase TET2. Our results showed that treatment with the DNA methyltransferase inhibitors 5-azacytidine (5-AzaC) and RG108 significantly increased ZO-1 expression in PAN-treated podocytes. Methylated DNA immunoprecipitation (MeDIP) and hydroxymethylated DNA immunoprecipitation (hMeDIP) results showed that TP regulates the methylation status of the ZO-1 promoter. Knockdown of TET2 decreased ZO-1 expression and increased methylation of its promoter, resulting in the increase of podocyte permeability. Altogether, these results indicate that TP upregulates the expression of ZO-1 and decreases podocyte permeability through TET2-mediated 5 mC demethylation. These findings suggest that TP may alleviate podocyte permeability through TET2-mediated hydroxymethylation of ZO-1.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Fenantrenos
/
Dioxigenases
/
Diterpenos
/
Compostos de Epóxi
/
Podócitos
/
Proteína da Zônula de Oclusão-1
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Exp Biol Med (Maywood)
Assunto da revista:
BIOLOGIA
/
FISIOLOGIA
/
MEDICINA
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
China