Usefulness of zebrafish larvae to evaluate drug-induced functional and morphological renal tubular alterations
Autor(a) principal: | |
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Data de Publicação: | 2018 |
Outros Autores: | , , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10362/151567 |
Resumo: | Prediction and management of drug-induced renal injury (DIRI) rely on the knowledge of the mechanisms of drug insult and on the availability of appropriate animal models to explore it. Zebrafish (Danio rerio) offers unique advantages for assessing DIRI because the larval pronephric kidney has a high homology with its human counterpart and it is fully mature at 3.5 days post-fertilization. Herein, we aimed to evaluate the usefulness of zebrafish larvae as a model of renal tubular toxicity through a comprehensive analysis of the renal alterations induced by the lethal concentrations for 10% of the larvae for gentamicin, paracetamol and tenofovir. We evaluated drug metabolic profile by mass spectrometry, renal function with the inulin clearance assay, the 3D morphology of the proximal convoluted tubule by two-photon microscopy and the ultrastructure of proximal convoluted tubule mitochondria by transmission electron microscopy. Paracetamol was metabolized by conjugation and oxidation with further detoxification with glutathione. Renal clearance was reduced with gentamicin and paracetamol. Proximal tubules were enlarged with paracetamol and tenofovir. All drugs induced mitochondrial alterations including dysmorphic shapes (“donuts”, “pancakes” and “rods”), mitochondrial swelling, cristae disruption and/or loss of matrix granules. These results are in agreement with the tubular effects of gentamicin, paracetamol and tenofovir in man and demonstrate that zebrafish larvae might be a good model to assess functional and structural damage associated with DIRI. © 2017 Springer-Verlag GmbH Germany |
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Usefulness of zebrafish larvae to evaluate drug-induced functional and morphological renal tubular alterationsMitochondriaNephrotoxicityProximal tubuleRenal clearanceZebrafishPrediction and management of drug-induced renal injury (DIRI) rely on the knowledge of the mechanisms of drug insult and on the availability of appropriate animal models to explore it. Zebrafish (Danio rerio) offers unique advantages for assessing DIRI because the larval pronephric kidney has a high homology with its human counterpart and it is fully mature at 3.5 days post-fertilization. Herein, we aimed to evaluate the usefulness of zebrafish larvae as a model of renal tubular toxicity through a comprehensive analysis of the renal alterations induced by the lethal concentrations for 10% of the larvae for gentamicin, paracetamol and tenofovir. We evaluated drug metabolic profile by mass spectrometry, renal function with the inulin clearance assay, the 3D morphology of the proximal convoluted tubule by two-photon microscopy and the ultrastructure of proximal convoluted tubule mitochondria by transmission electron microscopy. Paracetamol was metabolized by conjugation and oxidation with further detoxification with glutathione. Renal clearance was reduced with gentamicin and paracetamol. Proximal tubules were enlarged with paracetamol and tenofovir. All drugs induced mitochondrial alterations including dysmorphic shapes (“donuts”, “pancakes” and “rods”), mitochondrial swelling, cristae disruption and/or loss of matrix granules. These results are in agreement with the tubular effects of gentamicin, paracetamol and tenofovir in man and demonstrate that zebrafish larvae might be a good model to assess functional and structural damage associated with DIRI. © 2017 Springer-Verlag GmbH GermanyNOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)Centro de Estudos de Doenças Crónicas (CEDOC)RUNGorgulho, R.Jacinto, R.Lopes, S.S.Pereira, S.A.Tranfield, E.M.Martins, G.G.Gualda, E.J.Derks, R.J.E.Correia, A.C.Steenvoorden, E.Pintado, P.Mayboroda, O.A.Monteiro, E.C.Morello, J.2023-04-04T22:10:38Z2018-012018-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article13application/pdfhttp://hdl.handle.net/10362/151567eng0340-5761PURE: 3230807https://doi.org/10.1007/s00204-017-2063-1info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-07-10T16:13:20ZPortal AgregadorONG |
dc.title.none.fl_str_mv |
Usefulness of zebrafish larvae to evaluate drug-induced functional and morphological renal tubular alterations |
title |
Usefulness of zebrafish larvae to evaluate drug-induced functional and morphological renal tubular alterations |
spellingShingle |
Usefulness of zebrafish larvae to evaluate drug-induced functional and morphological renal tubular alterations Gorgulho, R. Mitochondria Nephrotoxicity Proximal tubule Renal clearance Zebrafish |
title_short |
Usefulness of zebrafish larvae to evaluate drug-induced functional and morphological renal tubular alterations |
title_full |
Usefulness of zebrafish larvae to evaluate drug-induced functional and morphological renal tubular alterations |
title_fullStr |
Usefulness of zebrafish larvae to evaluate drug-induced functional and morphological renal tubular alterations |
title_full_unstemmed |
Usefulness of zebrafish larvae to evaluate drug-induced functional and morphological renal tubular alterations |
title_sort |
Usefulness of zebrafish larvae to evaluate drug-induced functional and morphological renal tubular alterations |
author |
Gorgulho, R. |
author_facet |
Gorgulho, R. Jacinto, R. Lopes, S.S. Pereira, S.A. Tranfield, E.M. Martins, G.G. Gualda, E.J. Derks, R.J.E. Correia, A.C. Steenvoorden, E. Pintado, P. Mayboroda, O.A. Monteiro, E.C. Morello, J. |
author_role |
author |
author2 |
Jacinto, R. Lopes, S.S. Pereira, S.A. Tranfield, E.M. Martins, G.G. Gualda, E.J. Derks, R.J.E. Correia, A.C. Steenvoorden, E. Pintado, P. Mayboroda, O.A. Monteiro, E.C. Morello, J. |
author2_role |
author author author author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM) Centro de Estudos de Doenças Crónicas (CEDOC) RUN |
dc.contributor.author.fl_str_mv |
Gorgulho, R. Jacinto, R. Lopes, S.S. Pereira, S.A. Tranfield, E.M. Martins, G.G. Gualda, E.J. Derks, R.J.E. Correia, A.C. Steenvoorden, E. Pintado, P. Mayboroda, O.A. Monteiro, E.C. Morello, J. |
dc.subject.por.fl_str_mv |
Mitochondria Nephrotoxicity Proximal tubule Renal clearance Zebrafish |
topic |
Mitochondria Nephrotoxicity Proximal tubule Renal clearance Zebrafish |
description |
Prediction and management of drug-induced renal injury (DIRI) rely on the knowledge of the mechanisms of drug insult and on the availability of appropriate animal models to explore it. Zebrafish (Danio rerio) offers unique advantages for assessing DIRI because the larval pronephric kidney has a high homology with its human counterpart and it is fully mature at 3.5 days post-fertilization. Herein, we aimed to evaluate the usefulness of zebrafish larvae as a model of renal tubular toxicity through a comprehensive analysis of the renal alterations induced by the lethal concentrations for 10% of the larvae for gentamicin, paracetamol and tenofovir. We evaluated drug metabolic profile by mass spectrometry, renal function with the inulin clearance assay, the 3D morphology of the proximal convoluted tubule by two-photon microscopy and the ultrastructure of proximal convoluted tubule mitochondria by transmission electron microscopy. Paracetamol was metabolized by conjugation and oxidation with further detoxification with glutathione. Renal clearance was reduced with gentamicin and paracetamol. Proximal tubules were enlarged with paracetamol and tenofovir. All drugs induced mitochondrial alterations including dysmorphic shapes (“donuts”, “pancakes” and “rods”), mitochondrial swelling, cristae disruption and/or loss of matrix granules. These results are in agreement with the tubular effects of gentamicin, paracetamol and tenofovir in man and demonstrate that zebrafish larvae might be a good model to assess functional and structural damage associated with DIRI. © 2017 Springer-Verlag GmbH Germany |
publishDate |
2018 |
dc.date.none.fl_str_mv |
2018-01 2018-01-01T00:00:00Z 2023-04-04T22:10:38Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10362/151567 |
url |
http://hdl.handle.net/10362/151567 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
0340-5761 PURE: 3230807 https://doi.org/10.1007/s00204-017-2063-1 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
13 application/pdf |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
instname_str |
Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
instacron_str |
RCAAP |
institution |
RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
collection |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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1777303099091714048 |