Zebrafish Larvae Are a Suitable Model to Investigate the Metabolic Phenotype of Drug-Induced Renal Tubular Injury
| Autor: | Rico J. E. Derks, Sofia A. Pereira, Judit Morello, Emília C. Monteiro, Oleg A. Mayboroda, Evelyne Steenvoorden, Susana S. Lopes |
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| Přispěvatelé: | Centro de Estudos de Doenças Crónicas (CEDOC), NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM) |
| Jazyk: | angličtina |
| Předmět: |
0301 basic medicine
Drug media_common.quotation_subject renal tubular toxicity Biology Pharmacology Creatine Renal tubular toxicity 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Metabolomics Pharmacology (medical) kidney injury biomarkers Zebrafish Hypoxanthine translational models media_common Original Research lcsh:RM1-950 fungi biology.organism_classification Kidney injury biomarkers zebrafish metabolomics 3. Good health Mitochondria Glutamine mitochondria Protein catabolism 030104 developmental biology lcsh:Therapeutics. Pharmacology chemistry 030220 oncology & carcinogenesis Translational models Xenobiotic |
| Zdroj: | Frontiers in Pharmacology Frontiers in Pharmacology, 9 Frontiers in Pharmacology, Vol 9 (2018) Repositório Científico de Acesso Aberto de Portugal Repositório Científico de Acesso Aberto de Portugal (RCAAP) instacron:RCAAP |
| ISSN: | 1663-9812 |
| DOI: | 10.3389/fphar.2018.01193 |
| Popis: | This work was supported by the Calouste Gulbenkian Foundation, Gulbenkian Professorship 121986, 2012; the Foundation for Science and Technology of Portugal, mobility grant SFRH/BSAB/114291/2016 (to JM); and iNOVA4Health - UID/Multi/04462/2013, a program financially supported by Fundacao para a Ciencia e Tecnologia/Ministerio da Educacao e Ciencia, through national funds and co-funded by FEDER under the PT2020 Partnership Agreement. Prevention and treatment of drug-induced renal injury (DIRI) rely on the availability of sensitive and specific biomarkers of early kidney injury and predictive animal models of human pathophysiology. This study aimed to evaluate the potential of zebrafish larvae as translational model in metabolic profiling of DIRI. Zebrafish larvae were exposed to the lethal concentration for 10% of the larvae (LC10) or ½ LC10 of gentamicin, paracetamol and tenofovir as tenofovir disoproxil fumarate (TDF) and tenofovir (TFV). Metabolites were extracted from whole larvae and analyzed by liquid chromatography-mass spectrometry. Principal component analysis showed that drug exposition to the LC10 of paracetamol, TFV, and TDF was the main source of the variance of the data. To identify the metabolites responsible for the toxic effects of the drugs, partial least squares discriminant analyses were built between the LC10 and ½ LC10 for each drug. Features with variable importance in projection> 1.0 were selected and Venn diagrams were built to differentiate between the common and drug specific metabolites of DIRI. Creatine, tyrosine, glutamine, guanosine, hypoxanthine were identified as common metabolites, adenosine and tryptophan as paracetamol-specific and xanthine and oxidized glutathione as tenofovir-specific. Those metabolic changes can be associated with alterations in energy metabolism, xenobiotic detoxification and protein catabolism, all described in the human pathophysiology of DIRI. Thus, zebrafish proved to be a suitable model to characterize the metabolic changes associated with DIRI. This information can be useful to early diagnose DIRI and to improve our knowledge on the mechanisms of DIRI. publishersversion published |
| Databáze: | OpenAIRE |
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