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Biol. Med."],"abstract":"<jats:p>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\u00a0mC demethylation. These findings suggest that TP may alleviate podocyte permeability through TET2-mediated hydroxymethylation of ZO-1.<\/jats:p>","DOI":"10.3389\/ebm.2024.10051","type":"journal-article","created":{"date-parts":[[2024,5,31]],"date-time":"2024-05-31T04:11:44Z","timestamp":1717128704000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Triptolide decreases podocytes permeability by regulating TET2-mediated hydroxymethylation of ZO-1"],"prefix":"10.3389","volume":"249","author":[{"given":"Yue-Wen","family":"Tang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng-Ya","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia-Wei","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Wan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,5,31]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.kisu.2021.11.003","article-title":"Epidemiology of chronic kidney disease: an update 2022","volume":"12","author":"Kovesdy","year":"2022","journal-title":"Kidney Int Supplements"},{"key":"B2","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1159\/000516911","article-title":"From proteinuria to fibrosis: an update on pathophysiology and treatment options","volume":"46","author":"Sharma","year":"2021","journal-title":"Kidney Blood Press Res"},{"key":"B3","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1007\/978-981-13-8871-2_10","article-title":"Role of podocyte injury in glomerulosclerosis","volume":"1165","author":"Lu","year":"2019","journal-title":"Adv Exp Med Biol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"767","DOI":"10.7150\/thno.65948","article-title":"CXCR4 induces podocyte injury and proteinuria by activating \u03b2-catenin signaling","volume":"12","author":"Mo","year":"2022","journal-title":"Theranostics"},{"key":"B5","doi-asserted-by":"publisher","first-page":"755","DOI":"10.1083\/jcb.103.3.755","article-title":"Identification of ZO-1: a high molecular weight polypeptide associated with the tight junction (zonula occludens) in a variety of epithelia","volume":"103","author":"Stevenson","year":"1986","journal-title":"J Cel Biol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1091\/mbc.e11-09-0791","article-title":"Zonula occludens-1 and -2 regulate apical cell structure and the zonula adherens cytoskeleton in polarized epithelia","volume":"23","author":"Fanning","year":"2012","journal-title":"Mol Biol Cel"},{"key":"B7","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1111\/nyas.14798","article-title":"Tight junction proteins occludin and ZO-1 as regulators of epithelial proliferation and survival","volume":"1514","author":"Kuo","year":"2022","journal-title":"Ann N.Y Acad Sci"},{"key":"B8","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/j.yexcr.2015.12.001","article-title":"Puromycin aminonucleoside increases podocyte permeability by modulating ZO-1 in an oxidative stress-dependent manner","volume":"340","author":"Ha","year":"2016","journal-title":"Exp Cel Res"},{"key":"B9","doi-asserted-by":"publisher","first-page":"894","DOI":"10.2337\/diabetes.55.04.06.db05-0355","article-title":"Z\u039f-1 expression and phosphorylation in diabetic nephropathy","volume":"55","author":"Rincon-Choles","year":"2006","journal-title":"Diabetes"},{"key":"B10","doi-asserted-by":"publisher","first-page":"114470","DOI":"10.1016\/j.biopha.2023.114470","article-title":"Friend or foe? 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