Zebrafish (Danio rerio) larvae as a predictive model to study gentamicin-induced structural alterations of the kidney
Nephrotoxicity is an important drug safety aspect to be assessed during drug discovery and development. To study renal toxicity, in vitro cell-based assays are often used. Unfortunately, translating the results of such cell assays to vertebrates including human remains challenging. Therefore, we aim...
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description | Nephrotoxicity is an important drug safety aspect to be assessed during drug discovery and development. To study renal toxicity, in vitro 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 (SRμCT) 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, SRμCT- derived descriptors of glomerular and proximal tubular morphology and the histological analysis of mouse kidney biopsies. A combination of SRμCT 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. |
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To study renal toxicity, in vitro 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 (SRμCT) 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, SRμCT- derived descriptors of glomerular and proximal tubular morphology and the histological analysis of mouse kidney biopsies. A combination of SRμCT 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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0284562</identifier><identifier>PMID: 37079551</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Analysis ; Animal experimentation ; Animals ; Antibiotics ; Auroral kilometric radiation ; Biology and Life Sciences ; Biopsy ; Cell culture ; Computed tomography ; Confocal microscopy ; Danio rerio ; Drug discovery ; Engineering and Technology ; Ethanol ; Evaluation ; Experiments ; Fluorescence ; Gentamicin ; Gentamicins - toxicity ; Glomerulus ; Histology ; Humans ; Kidney - diagnostic imaging ; Kidney - pathology ; Kidney Diseases - pathology ; Kidney Glomerulus - pathology ; Kidneys ; Larva ; Larvae ; Lasers ; Mammals ; Medicine and Health Sciences ; Mice ; Microscopy ; Modelling ; Morphology ; Pharmacovigilance ; Prediction models ; Proximal tubules ; Radiation ; Radiation damage ; Research and Analysis Methods ; Screening ; Synchrotron radiation ; Synchrotrons ; Toxicity ; Transgenic mice ; Vertebrates ; Zebra fish ; Zebrafish</subject><ispartof>PloS one, 2023-04, Vol.18 (4), p.e0284562-e0284562</ispartof><rights>Copyright: © 2023 Bolten et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</rights><rights>COPYRIGHT 2023 Public Library of Science</rights><rights>2023 Bolten et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2023 Bolten et al 2023 Bolten et al</rights><rights>2023 Bolten et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c594t-de1ce485fc20df4a5243988100b4ac85ff9ae2c72ee17ebcf6b9efe303ff9b6b3</citedby><cites>FETCH-LOGICAL-c594t-de1ce485fc20df4a5243988100b4ac85ff9ae2c72ee17ebcf6b9efe303ff9b6b3</cites><orcidid>0000-0002-0374-0472 ; 0000-0003-1748-5676</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10118166/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10118166/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,724,777,781,861,882,2096,2915,23847,27905,27906,53772,53774,79349,79350</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37079551$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Máthé, Domokos</contributor><creatorcontrib>Bolten, Jan Stephan</creatorcontrib><creatorcontrib>Tanner, Christine</creatorcontrib><creatorcontrib>Rodgers, Griffin</creatorcontrib><creatorcontrib>Schulz, Georg</creatorcontrib><creatorcontrib>Levano, Soledad</creatorcontrib><creatorcontrib>Weitkamp, Timm</creatorcontrib><creatorcontrib>Waldner, Samuel</creatorcontrib><creatorcontrib>Puligilla, Ramya Deepthi</creatorcontrib><creatorcontrib>Bodmer, Daniel</creatorcontrib><creatorcontrib>Müller, Bert</creatorcontrib><creatorcontrib>Huwyler, Jörg</creatorcontrib><title>Zebrafish (Danio rerio) larvae as a predictive model to study gentamicin-induced structural alterations of the kidney</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Nephrotoxicity is an important drug safety aspect to be assessed during drug discovery and development. 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(Danio rerio) larvae as a predictive model to study gentamicin-induced structural alterations of the kidney</title><author>Bolten, Jan Stephan ; Tanner, Christine ; Rodgers, Griffin ; Schulz, Georg ; Levano, Soledad ; Weitkamp, Timm ; Waldner, Samuel ; Puligilla, Ramya Deepthi ; Bodmer, Daniel ; Müller, Bert ; Huwyler, Jörg</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c594t-de1ce485fc20df4a5243988100b4ac85ff9ae2c72ee17ebcf6b9efe303ff9b6b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Analysis</topic><topic>Animal experimentation</topic><topic>Animals</topic><topic>Antibiotics</topic><topic>Auroral kilometric radiation</topic><topic>Biology and Life Sciences</topic><topic>Biopsy</topic><topic>Cell culture</topic><topic>Computed tomography</topic><topic>Confocal microscopy</topic><topic>Danio rerio</topic><topic>Drug discovery</topic><topic>Engineering and 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One</addtitle><date>2023-04-20</date><risdate>2023</risdate><volume>18</volume><issue>4</issue><spage>e0284562</spage><epage>e0284562</epage><pages>e0284562-e0284562</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Nephrotoxicity is an important drug safety aspect to be assessed during drug discovery and development. To study renal toxicity, in vitro 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 (SRμCT) 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, SRμCT- derived descriptors of glomerular and proximal tubular morphology and the histological analysis of mouse kidney biopsies. A combination of SRμCT 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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>37079551</pmid><doi>10.1371/journal.pone.0284562</doi><orcidid>https://orcid.org/0000-0002-0374-0472</orcidid><orcidid>https://orcid.org/0000-0003-1748-5676</orcidid><oa>free_for_read</oa></addata></record> |
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source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS); PubMed Central; Free Full-Text Journals in Chemistry |
subjects | Analysis Animal experimentation Animals Antibiotics Auroral kilometric radiation Biology and Life Sciences Biopsy Cell culture Computed tomography Confocal microscopy Danio rerio Drug discovery Engineering and Technology Ethanol Evaluation Experiments Fluorescence Gentamicin Gentamicins - toxicity Glomerulus Histology Humans Kidney - diagnostic imaging Kidney - pathology Kidney Diseases - pathology Kidney Glomerulus - pathology Kidneys Larva Larvae Lasers Mammals Medicine and Health Sciences Mice Microscopy Modelling Morphology Pharmacovigilance Prediction models Proximal tubules Radiation Radiation damage Research and Analysis Methods Screening Synchrotron radiation Synchrotrons Toxicity Transgenic mice Vertebrates Zebra fish Zebrafish |
title | Zebrafish (Danio rerio) larvae as a predictive model to study gentamicin-induced structural alterations of the kidney |
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