{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T03:33:51Z","timestamp":1790393631391,"version":"4.1.0"},"reference-count":72,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,3,25]],"date-time":"2023-03-25T00:00:00Z","timestamp":1679702400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004543","name":"China Scholarship Council","doi-asserted-by":"publisher","award":["201806910081"],"award-info":[{"award-number":["201806910081"]}],"id":[{"id":"10.13039\/501100004543","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004543","name":"China Scholarship Council","doi-asserted-by":"publisher","award":["CP1805"],"award-info":[{"award-number":["CP1805"]}],"id":[{"id":"10.13039\/501100004543","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004543","name":"China Scholarship Council","doi-asserted-by":"publisher","award":["184.034.019"],"award-info":[{"award-number":["184.034.019"]}],"id":[{"id":"10.13039\/501100004543","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002997","name":"Dutch Kidney Foundation","doi-asserted-by":"publisher","award":["201806910081"],"award-info":[{"award-number":["201806910081"]}],"id":[{"id":"10.13039\/501100002997","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002997","name":"Dutch Kidney Foundation","doi-asserted-by":"publisher","award":["CP1805"],"award-info":[{"award-number":["CP1805"]}],"id":[{"id":"10.13039\/501100002997","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002997","name":"Dutch Kidney Foundation","doi-asserted-by":"publisher","award":["184.034.019"],"award-info":[{"award-number":["184.034.019"]}],"id":[{"id":"10.13039\/501100002997","id-type":"DOI","asserted-by":"publisher"}]},{"name":"University Medical Center Utrecht and The Netherlands X-omics Initiative","award":["201806910081"],"award-info":[{"award-number":["201806910081"]}]},{"name":"University Medical Center Utrecht and The Netherlands X-omics Initiative","award":["CP1805"],"award-info":[{"award-number":["CP1805"]}]},{"name":"University Medical Center Utrecht and The Netherlands X-omics Initiative","award":["184.034.019"],"award-info":[{"award-number":["184.034.019"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>Kidney fibrosis is the common final pathway of nearly all chronic and progressive nephropathies. One cause may be the accumulation of senescent cells that secrete factors (senescence associated secretory phenotype, SASP) promoting fibrosis and inflammation. It has been suggested that uremic toxins, such as indoxyl sulfate (IS), play a role in this. Here, we investigated whether IS accelerates senescence in conditionally immortalized proximal tubule epithelial cells overexpressing the organic anion transporter 1 (ciPTEC-OAT1), thereby promoting kidney fibrosis. Cell viability results suggested that the tolerance of ciPTEC-OAT1 against IS increased in a time-dependent manner at the same dose of IS. This was accompanied by SA-\u03b2-gal staining, confirming the accumulation of senescent cells, as well as an upregulation of p21 and downregulation of laminB1 at different time points, accompanied by an upregulation in the SASP factors IL-1\u03b2, IL-6 and IL-8. RNA-sequencing and transcriptome analysis revealed that IS accelerates senescence, and that cell cycle appears to be the most relevant factor during the process. IS accelerates senescence via TNF-\u03b1 and NF-\u0138B signalling early on, and the epithelial-mesenchymal transition process at later time points. In conclusion, our results suggest that IS accelerates cellular senescence in proximal tubule epithelial cells.<\/jats:p>","DOI":"10.3390\/toxins15040242","type":"journal-article","created":{"date-parts":[[2023,3,27]],"date-time":"2023-03-27T02:18:27Z","timestamp":1679883507000},"page":"242","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["The Uremic Toxin Indoxyl Sulfate Accelerates Senescence in Kidney Proximal Tubule Cells"],"prefix":"10.3390","volume":"15","author":[{"given":"Yi","family":"Yang","sequence":"first","affiliation":[{"name":"Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6120-5200","authenticated-orcid":false,"given":"Milos","family":"Mihajlovic","sequence":"additional","affiliation":[{"name":"Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0544-8096","authenticated-orcid":false,"given":"Manoe J.","family":"Janssen","sequence":"additional","affiliation":[{"name":"Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1560-1074","authenticated-orcid":false,"given":"Rosalinde","family":"Masereeuw","sequence":"additional","affiliation":[{"name":"Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/s11926-018-0712-x","article-title":"Targeting Senescent Cells in Fibrosis: Pathology, Paradox, and Practical Considerations","volume":"20","author":"Schafer","year":"2018","journal-title":"Curr. 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