{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T08:46:48Z","timestamp":1785746808531,"version":"3.56.0"},"reference-count":67,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Momentum EU","award":["101286954"],"award-info":[{"award-number":["101286954"]}]},{"name":"Swedish Medical Research Counci","award":["2018-00932"],"award-info":[{"award-number":["2018-00932"]}]},{"name":"Heart and Lung Foundation","award":["20230231"],"award-info":[{"award-number":["20230231"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>Chronic kidney disease is associated with neurovascular complications including cognitive impairment, potentially involving blood\u2013brain barrier (BBB) impairment. The protein-bound uremic toxin indoxyl sulfate (IS) promotes endothelial injury, but its effects on human brain microvascular endothelial cells remain incompletely understood. Human cerebral microvascular endothelial cells (hCMEC\/D3) were exposed to IS 200 and 900 \u03bcM. BBB integrity was assessed by the FITC-dextran (4 kDa) transwell permeability assay and claudin-5 immunofluorescence. Transcriptional responses were quantified by qPCR for aryl hydrocarbon (AhR) target genes, oxidative stress-associated and inflammatory markers, senescence, and junction-associated genes. Senescence-associated phenotypic changes were evaluated by SA-\u03b2-galactosidase staining and cytokine array profiling. IS increased endothelial permeability at 24 and 48 h (~1.5-fold relative to control) without evidence of cytotoxicity and reduced claudin-5 staining intensity. IS strongly upregulated AhR target genes, including CYP1A1, CYP1B1, and CYP1A2. NFE2L2 and IDO1 increased, while NFKB1 remained unchanged. SA-\u03b2-gal positivity increased, accompanied by elevated GM-CSF and G-CSF secretion, while CDKN1A decreased at IS 900 \u00b5M and CDKN2A remained unchanged. CDH5 was downregulated, TJP1 increased at 900 \u00b5M, and CLDN5 remained unchanged. These findings indicate that IS exposure is associated with impaired BBB integrity, AhR-related transcriptional responses, oxidative stress-associated transcriptional changes, junctional remodeling, and senescence-like endothelial features. However, causal attribution to individual pathways requires inhibition or knockdown studies.<\/jats:p>","DOI":"10.3390\/toxins18080334","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T08:04:59Z","timestamp":1785744299000},"page":"334","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Indoxyl Sulfate-Mediated Blood\u2013Brain Barrier Damage in Chronic Kidney Disease"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7443-1626","authenticated-orcid":false,"given":"Leah","family":"Hernandez","sequence":"first","affiliation":[{"name":"Division of Renal Medicine, Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, 141 52 Huddinge, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camillo Tancredi","family":"Strizzi","sequence":"additional","affiliation":[{"name":"Division of Renal Medicine, Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, 141 52 Huddinge, Sweden"},{"name":"Department of Translational Medicine and Surgery, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"},{"name":"Nephrology, Dialysis and Transplantation Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-4919-3133","authenticated-orcid":false,"given":"Miriam","family":"Rosina","sequence":"additional","affiliation":[{"name":"Department of of Translational Medicine (DIMET), University of Piemonte Orientale (UPO), 28100 Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-7828-9260","authenticated-orcid":false,"given":"Angelina","family":"Schwarz","sequence":"additional","affiliation":[{"name":"Division of Renal Medicine, Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, 141 52 Huddinge, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Kronqvist","sequence":"additional","affiliation":[{"name":"Department of Medicine, Karolinska Institutet, 141 83 Huddinge, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8050-9100","authenticated-orcid":false,"given":"Samsul","family":"Arefin","sequence":"additional","affiliation":[{"name":"Division of Renal Medicine, Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, 141 52 Huddinge, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8785-4820","authenticated-orcid":false,"given":"Peter","family":"Stenvinkel","sequence":"additional","affiliation":[{"name":"Division of Renal Medicine, Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, 141 52 Huddinge, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4841-6836","authenticated-orcid":false,"given":"Karolina","family":"Kublickiene","sequence":"additional","affiliation":[{"name":"Division of Renal Medicine, Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, 141 52 Huddinge, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1016\/j.kint.2019.07.012","article-title":"A Single Number for Advocacy and Communication\u2014Worldwide More than 850 Million Individuals Have Kidney Diseases","volume":"96","author":"Jager","year":"2019","journal-title":"Kidney Int."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Graboski, A.L., and Redinbo, M.R. 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