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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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Autores principales: Bolten, Jan Stephan, Tanner, Christine, Rodgers, Griffin, Schulz, Georg, Levano, Soledad, Weitkamp, Timm, Waldner, Samuel, Puligilla, Ramya Deepthi, Bodmer, Daniel, Müller, Bert, Huwyler, Jörg
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10118166/
https://www.ncbi.nlm.nih.gov/pubmed/37079551
http://dx.doi.org/10.1371/journal.pone.0284562
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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_facet 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 Bolten, Jan Stephan
collection PubMed
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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spelling pubmed-101181662023-04-21 Zebrafish (Danio rerio) larvae as a predictive model to study gentamicin-induced structural alterations of the kidney Bolten, Jan Stephan Tanner, Christine Rodgers, Griffin Schulz, Georg Levano, Soledad Weitkamp, Timm Waldner, Samuel Puligilla, Ramya Deepthi Bodmer, Daniel Müller, Bert Huwyler, Jörg PLoS One Research Article 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. Public Library of Science 2023-04-20 /pmc/articles/PMC10118166/ /pubmed/37079551 http://dx.doi.org/10.1371/journal.pone.0284562 Text en © 2023 Bolten et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Bolten, Jan Stephan
Tanner, Christine
Rodgers, Griffin
Schulz, Georg
Levano, Soledad
Weitkamp, Timm
Waldner, Samuel
Puligilla, Ramya Deepthi
Bodmer, Daniel
Müller, Bert
Huwyler, Jörg
Zebrafish (Danio rerio) larvae as a predictive model to study gentamicin-induced structural alterations of the kidney
title Zebrafish (Danio rerio) larvae as a predictive model to study gentamicin-induced structural alterations of the kidney
title_full Zebrafish (Danio rerio) larvae as a predictive model to study gentamicin-induced structural alterations of the kidney
title_fullStr Zebrafish (Danio rerio) larvae as a predictive model to study gentamicin-induced structural alterations of the kidney
title_full_unstemmed Zebrafish (Danio rerio) larvae as a predictive model to study gentamicin-induced structural alterations of the kidney
title_short Zebrafish (Danio rerio) larvae as a predictive model to study gentamicin-induced structural alterations of the kidney
title_sort zebrafish (danio rerio) larvae as a predictive model to study gentamicin-induced structural alterations of the kidney
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10118166/
https://www.ncbi.nlm.nih.gov/pubmed/37079551
http://dx.doi.org/10.1371/journal.pone.0284562
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