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Although proximal tubular accumulation mediated by megalin is well established, the downstream cellular response is still incompletely understood. Here, we compared repeated-dose transcriptomic responses to gentamicin and tobramycin in a panel of human proximal tubular models comprising primary proximal tubular epithelial cells (PTEC; three donors), human iPSC-derived proximal tubular-like cells (PTL; three donors), RPTEC\/TERT1 cells, and HK-2 cells. Cells were exposed daily for seven days to 12, 250, or 450\u00a0\u00b5g\/mL gentamicin or tobramycin, and gene expression was assessed using the TempO-Seq EU-ToxRisk v2.1 panel followed by DESeq2 analysis. Primary PTEC and PTL showed the clearest and most coherent response, characterised by strong induction of interferon-stimulated genes including IFI27, IFI6, IFIT1-3, ISG15, MX1, OAS1, UBE2L6, USP18, IFI44L, HERC6, and RSAD2. Targeted regulator analysis showed strong enrichment of overlapping ISGF3, IRF7, and IRF1 target networks, consistent with a dominant interferon-stimulated gene program, together with a smaller NF-\u03baB-associated inflammatory branch. In contrast, RPTEC\/TERT1 and HK-2 cells showed weaker and less coherent responses. Tobramycin generally induced a stronger and more consistent transcriptional response than gentamicin across responsive models. These data identify a robust innate immune-like transcriptional signature in human proximal tubular models following repeated aminoglycoside exposure and support primary PTEC and PTL as more informative in vitro systems for mechanistic investigation of aminoglycoside nephrotoxicity.<\/jats:p>","DOI":"10.1007\/s00204-026-04494-w","type":"journal-article","created":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T13:29:04Z","timestamp":1784035744000},"page":"5211-5223","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Repeated aminoglycoside exposure activates interferon-stimulated genes in human renal proximal tubular models"],"prefix":"10.1007","volume":"100","author":[{"given":"Vidya","family":"Chandrasekaran","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamara","family":"Meijer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin O.","family":"Leonard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anja","family":"Wilmes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6860-2898","authenticated-orcid":false,"given":"Paul","family":"Jennings","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,14]]},"reference":[{"key":"4494_CR1","doi-asserted-by":"publisher","first-page":"606392","DOI":"10.3389\/fphys.2021.606392","volume":"12","author":"AH Albino","year":"2021","unstructured":"Albino AH, Zambom FFF, Foresto-Neto O et al (2021) Renal inflammation and innate immune activation underlie the transition from gentamicin-induced acute kidney injury to renal fibrosis. 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