{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T06:55:15Z","timestamp":1781765715177,"version":"3.54.5"},"reference-count":78,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T00:00:00Z","timestamp":1781654400000},"content-version":"vor","delay-in-days":167,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Toxicology"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:p>As a heavy metal and alpha emitter, uranium U(VI) presents chemical and radiological toxicity risks. Its toxicity particularly targets the kidneys in the event of intoxication, but the detailed study mechanisms leading to uranium\u2010induced renal failure have not yet been studied based on the adverse outcome pathway (AOP) approach. Using a well\u2010specialized in vitro model of renal proximal tubule epithelial cells (hRPTEC TERT1), this research aims to contribute to the development of the AOP of kidney toxicity. After identifying the U(VI) concentrations that induce deleterious effects (apoptosis and necrosis\/cytotoxicity), key events linked to oxidative stress, apoptosis, survival, inflammation, and kidney toxicity are studied at the gene and protein levels. Apoptosis (Caspase 3\/7 activity) is induced starting from exposure to 300\u2009\u03bcM and necrosis (LDH assay) from 500\u2009\u03bcM with a rate of 60%. hRPTEC cells have an IC50 of 420\u2009\u03bcM after 48\u2009h\u2009U(VI) exposure. Uranium induces an early 2\u2010fold rise in ROS production, and an antioxidant response was observed accordingly. Cell survival signaling appeared to be enhanced at 100\u2009\u03bcM, while higher concentrations (&gt; 300\u2009\u03bcM) induced a marked inflammatory response, with increased levels of TNF\u03b1 (6,5\u2010fold), IL\u20106, and IL\u201018, leading to a 16% increase in caspase 3\/7 at 300\u2009\u03bcM and LDH at 500\u2009\u03bcM. A slight increase of 22% in the KIM\u20101 protein level is observed at 500\u2009\u03bcM, and limited changes occurred for other nephrotoxicity biomarkers. In conclusion, this exploratory work generated a multiplex panel detailing the key events in the AOP of uranium\u2010induced renal failure (Graphical Abstract). This panel features a human phenotype of renal proximal tubule epithelial cells, the preferential target of uranium in the kidney, while also considering the dose\u2010dependent effects.<\/jats:p>","DOI":"10.1155\/jt\/6692188","type":"journal-article","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T06:22:34Z","timestamp":1781763754000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["In Vitro hRPTEC TERT1 Model for Uranium\u2010Induced Nephrotoxicity Pathway 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