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The uremic toxins indoxyl sulfate (IS) and p-cresol (PC) accumulate in the plasma of chronic kidney disease (CKD) patients, causing accelerated endothelial aging, increased cardiovascular events and mortality. However, the mechanisms by which uremic toxins exert their deleterious effects on endothelial aging are not yet fully known. Thus, the aim of the present study is to determine the effects of IS and PC on endothelial damage and early senescence in cultured human umbilical vein endothelial cells (HUVECs). Hence, we establish an in vitro model of endothelial damage mediated by different passages of HUVECs and stimulated with different concentrations of IS and PC to evaluate functional effects on the vascular endothelium. We observe that cell passage-induced senescence is associated with apoptosis, ROS production and decreased endothelial proliferative capacity. Similarly, we observe that IS and PC cause premature aging in a dose-dependent manner, altering HUVECs\u2019 regenerative capacity, and decreasing their cell migration and potential to form vascular structures in vitro. In conclusion, IS and PC cause accelerated aging in HUVECs, thus contributing to endothelial dysfunction associated with CKD progression.<\/jats:p>","DOI":"10.3390\/toxins13100738","type":"journal-article","created":{"date-parts":[[2021,10,20]],"date-time":"2021-10-20T22:07:04Z","timestamp":1634767624000},"page":"738","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Passage Number-Induced Replicative Senescence Modulates the Endothelial Cell Response to Protein-Bound Uremic Toxins"],"prefix":"10.3390","volume":"13","author":[{"given":"Fatima","family":"Guerrero","sequence":"first","affiliation":[{"name":"Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Reina Sofia University Hospital, University of Cordoba, 14004 C\u00f3rdoba, Spain"},{"name":"Department of Medicine, University of Cordoba, 14004 C\u00f3rdoba, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andres","family":"Carmona","sequence":"additional","affiliation":[{"name":"Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Reina Sofia University Hospital, University of Cordoba, 14004 C\u00f3rdoba, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Jose","family":"Jimenez","sequence":"additional","affiliation":[{"name":"Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Reina Sofia University Hospital, University of Cordoba, 14004 C\u00f3rdoba, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Obrero","sequence":"additional","affiliation":[{"name":"Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Reina Sofia University Hospital, University of Cordoba, 14004 C\u00f3rdoba, Spain"},{"name":"Department of Medicine, University of Cordoba, 14004 C\u00f3rdoba, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Pulido","sequence":"additional","affiliation":[{"name":"Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Reina Sofia University Hospital, University of Cordoba, 14004 C\u00f3rdoba, Spain"},{"name":"Department of Medicine, University of Cordoba, 14004 C\u00f3rdoba, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Antonio","family":"Moreno","sequence":"additional","affiliation":[{"name":"Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Reina Sofia University Hospital, University of Cordoba, 14004 C\u00f3rdoba, Spain"},{"name":"Department of Cell Biology, Physiology and Immunology, University of Cordoba, 14014 C\u00f3rdoba, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sagrario","family":"Soriano","sequence":"additional","affiliation":[{"name":"Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Reina Sofia University Hospital, University of Cordoba, 14004 C\u00f3rdoba, Spain"},{"name":"Nephrology Unit, Reina Sofia University Hospital, 14004 C\u00f3rdoba, Spain"},{"name":"Spanish Renal Research Network, Institute of Health Carlos III, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8010-7187","authenticated-orcid":false,"given":"Alejandro","family":"Mart\u00edn-Malo","sequence":"additional","affiliation":[{"name":"Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Reina Sofia University Hospital, University of Cordoba, 14004 C\u00f3rdoba, Spain"},{"name":"Department of Medicine, University of Cordoba, 14004 C\u00f3rdoba, Spain"},{"name":"Nephrology Unit, Reina Sofia University Hospital, 14004 C\u00f3rdoba, Spain"},{"name":"Spanish Renal Research Network, Institute of Health Carlos III, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedro","family":"Aljama","sequence":"additional","affiliation":[{"name":"Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Reina Sofia University Hospital, University of Cordoba, 14004 C\u00f3rdoba, Spain"},{"name":"Department of Medicine, University of Cordoba, 14004 C\u00f3rdoba, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Cunha, R.S.D., Santos, A.F., Barreto, F.C., and Stinghen, A.E.M. 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