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.
Download full-text PDF |
Source |
---|---|
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11176508 | PMC |
http://dx.doi.org/10.3389/ebm.2024.10051 | DOI Listing |
Kidney Med
December 2024
Department of Medicine, New York University Langone School of Medicine, New York, NY.
Theranostics
December 2024
Department of Pediatrics, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Zhejiang Chinese Medical University, Hangzhou 310006, China.
Childhood nephrotic syndrome (NS) is a serious disease affecting the health and quality of life of children, which is characterized by a series of pathophysiological changes due to the increased permeability of the glomerular membrane to plasma proteins. Low renal drug distribution and inefficient cellular uptake, resulting from cellular dysfunctions of filtration and internalization, are the main barriers to drug treatment in childhood NS, leading to deterioration in nephropathy. However, efficient therapeutic methods against childhood NS are still lacking in clinic.
View Article and Find Full Text PDFFront Nephrol
October 2024
Tareev Clinic of Internal Diseases, Sechenov First Moscow State Medical University, Moscow, Russia.
Pediatr Neonatol
October 2024
Department of Pediatrics, Kansai Medical University, 2-5-1, Shin-machi, Hirakata, Osaka, 573 1010, Japan. Electronic address:
Idiopathic nephrotic syndrome (INS) is a relatively common renal disorder of childhood characterized by severe proteinuria and associated hypoproteinemia and edema. Although the pathogenesis of INS remains unknown, the prevailing theory of its pathogenesis is as follows. Antigenic stimulation, such as viral infections or vaccines, in children with susceptibility factors for INS triggers abnormal immune responses, resulting in production of pathogenic substances that injure podocytes (renal glomerular epithelial cells).
View Article and Find Full Text PDFJ Clin Med
October 2024
Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, Borowska 213, 50-367 Wrocław, Poland.
The endothelin system is reported to play a significant role in glomerular and tubulointerstitial kidney disease. In the kidney, endothelins are produced in mesangial cells and the glomerular basement membrane by the endothelium and podocytes. The endothelin system regulates glomerular function by inducing proliferation, increasing permeability and in effect proteinuria, and stimulating inflammation, tubular fibrosis, and glomerular scarring.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!