{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T20:37:07Z","timestamp":1779914227816,"version":"3.53.1"},"reference-count":47,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2023,4,20]],"date-time":"2023-04-20T00:00:00Z","timestamp":1681948800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100011039","name":"Swiss Centre for Applied Human Toxicology","doi-asserted-by":"publisher","award":["(SCAHT-GL 21-09"],"award-info":[{"award-number":["(SCAHT-GL 21-09"]}],"id":[{"id":"10.13039\/501100011039","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","award":["ANR-11-EQPX-0031"],"award-info":[{"award-number":["ANR-11-EQPX-0031"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Nephrotoxicity is an important drug safety aspect to be assessed during drug discovery and development. To study renal toxicity, <jats:italic>in vitro<\/jats:italic> cell-based assays are often used. Unfortunately, translating the results of such cell assays to vertebrates including human remains challenging. Therefore, we aim to evaluate whether zebrafish larvae (ZFL) could serve as a vertebrate screening model to detect gentamicin-induced changes of kidney glomeruli and proximal tubules. To validate the model, we compared the results of ZFL with those obtained from kidney biopsies of gentamicin-treated mice. We used transgenic zebrafish lines expressing enhanced green fluorescent proteins in the glomerulus to visualize glomerular damage. Synchrotron radiation-based computed tomography (SR\u03bcCT) is a label-free approach providing three-dimensional representations of renal structures with micrometre resolution. Clinically used gentamicin concentrations induce nephrotoxicity and affect glomerular and proximal tubular morphology. Findings were confirmed in mice and ZFL. There was a strong correlation between fluorescent signals in ZFL, SR\u03bcCT- derived descriptors of glomerular and proximal tubular morphology and the histological analysis of mouse kidney biopsies. A combination of SR\u03bcCT and confocal microscopy provides unprecedented insights into anatomical structures of the zebrafish kidney. Based on our findings, we suggest to use ZFL as a predictive vertebrate screening model to study drug-induced nephrotoxicity and to bridge the gap between cell culture-based test systems and experiments in mammals.<\/jats:p>","DOI":"10.1371\/journal.pone.0284562","type":"journal-article","created":{"date-parts":[[2023,4,20]],"date-time":"2023-04-20T17:58:10Z","timestamp":1682013490000},"page":"e0284562","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":11,"title":["Zebrafish (Danio rerio) larvae as a predictive model to study gentamicin-induced structural alterations of the kidney"],"prefix":"10.1371","volume":"18","author":[{"given":"Jan Stephan","family":"Bolten","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Tanner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Griffin","family":"Rodgers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georg","family":"Schulz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soledad","family":"Levano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0374-0472","authenticated-orcid":true,"given":"Timm","family":"Weitkamp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Waldner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramya 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Hard X-ray microtomography of Zebrafish larvae. International Conference on X-Ray Lasers 2020. SPIE; 2021. pp. 308\u2013322.","DOI":"10.1117\/12.2593119"},{"key":"pone.0284562.ref027","doi-asserted-by":"crossref","unstructured":"Osterwalder M, Bolten JS, Rodgers G, Schulz G, Tanner C, C\u00f6rek E, et al. Three-dimensional x-ray microscopy of zebrafish larvae. Bioinspiration, Biomimetics, and Bioreplication XI. 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Design of Indirect X-Ray Detectors for Tomography on the Anatomix Beamline. Proc Mech EngDesign Synchrotron Radiat Equip Instrum. 2018;MEDSI2018: 3 pages, 0.999 MB."},{"key":"pone.0284562.ref032","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1046\/j.1365-2818.2002.01010.x","article-title":"Simultaneous phase and amplitude extraction from a single defocused image of a homogeneous object","volume":"206","author":"D Paganin","year":"2002","journal-title":"J Microsc"},{"key":"pone.0284562.ref033","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.nimb.2013.09.030","article-title":"The PyHST2 hybrid distributed code for high speed tomographic reconstruction with iterative reconstruction and a priori knowledge capabilities","volume":"324","author":"A Mirone","year":"2014","journal-title":"Nucl Instrum Methods Phys Res Sect B Beam Interact Mater At"},{"issue":"No 66\u201371","key":"pone.0284562.ref034","article-title":"Dimensionality Reduction: A Comparative Review","volume":"Vol 10","author":"L. van der Maaten","journal-title":"J Mach Learn Res"},{"key":"pone.0284562.ref035","doi-asserted-by":"crossref","first-page":"1120","DOI":"10.1038\/ki.2008.37","article-title":"The zebrafish pronephros: A model to study nephron segmentation","volume":"73","author":"RA Wingert","year":"2008","journal-title":"Kidney Int"},{"key":"pone.0284562.ref036","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1089\/zeb.2017.1527","article-title":"The Efficacy of Puromycin and Adriamycin for Induction of Glomerular Failure in Larval Zebrafish Validated by an Assay of Glomerular Permeability Dynamics","volume":"15","author":"SA Rider","year":"2018","journal-title":"Zebrafish"},{"key":"pone.0284562.ref037","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.1016\/j.clinthera.2021.04.011","article-title":"Aminoglycosides in Critically Ill Septic Patients With Acute Kidney Injury Receiving Continuous Renal Replacement Therapy: A Multicenter, Observational Study","volume":"43","author":"A Boyer","year":"2021","journal-title":"Clin Ther"},{"key":"pone.0284562.ref038","doi-asserted-by":"crossref","first-page":"1832","DOI":"10.1128\/AAC.36.9.1832","article-title":"Effect of concomitant administration of piperacillin on the dispositions of isepamicin and gentamicin in patients with end-stage renal disease","volume":"36","author":"CE Halstenson","year":"1992","journal-title":"Antimicrob Agents Chemother"},{"key":"pone.0284562.ref039","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1016\/j.cbpc.2010.02.004","article-title":"Nephrotoxicity assessments of acetaminophen during zebrafish embryogenesis","volume":"151","author":"H-C Peng","year":"2010","journal-title":"Comp Biochem Physiol Part C Toxicol Pharmacol"},{"key":"pone.0284562.ref040","doi-asserted-by":"crossref","first-page":"e82137","DOI":"10.1371\/journal.pone.0082137","article-title":"Development of an Automated Imaging Pipeline for the Analysis of the Zebrafish Larval Kidney","volume":"8","author":"JH Westhoff","year":"2013","journal-title":"PLoS 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