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Capturing time-dependent activation of genes and stress-response pathways using transcriptomics in iPSC-derived renal proximal tubule cells.
Jennings, Paul; Carta, Giada; Singh, Pranika; da Costa Pereira, Daniel; Feher, Anita; Dinnyes, Andras; Exner, Thomas E; Wilmes, Anja.
Afiliación
  • Jennings P; Division of Molecular and Computational Toxicology, Chemistry and Pharmaceutical Sciences, AIMMS, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
  • Carta G; Division of Molecular and Computational Toxicology, Chemistry and Pharmaceutical Sciences, AIMMS, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
  • Singh P; Edelweiss Connect GmbH, Technology Park Basel, Hochbergerstrasse 60C, 4057, Basel, Switzerland.
  • da Costa Pereira D; Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland.
  • Feher A; Division of Molecular and Computational Toxicology, Chemistry and Pharmaceutical Sciences, AIMMS, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
  • Dinnyes A; BioTalentum Ltd, Aulich Lajos Street 26, Gödöllo, 2100, Hungary.
  • Exner TE; BioTalentum Ltd, Aulich Lajos Street 26, Gödöllo, 2100, Hungary.
  • Wilmes A; HCEMM-USZ Stem Cell Research Group, Hungarian Centre of Excellence for Molecular Medicine, Szeged, 6723, Hungary.
Cell Biol Toxicol ; 39(4): 1773-1793, 2023 08.
Article en En | MEDLINE | ID: mdl-36586010
ABSTRACT
Transcriptomic analysis is a powerful method in the utilization of New Approach Methods (NAMs) for identifying mechanisms of toxicity and application to hazard characterization. With this regard, mapping toxicological events to time of exposure would be helpful to characterize early events. Here, we investigated time-dependent changes in gene expression levels in iPSC-derived renal proximal tubular-like cells (PTL) treated with five diverse compounds using TempO-Seq transcriptomics with the aims to evaluate the application of PTL for toxicity prediction and to report on temporal effects for the activation of cellular stress response pathways. PTL were treated with either 50 µM amiodarone, 10 µM sodium arsenate, 5 nM rotenone, or 300 nM tunicamycin over a temporal time course between 1 and 24 h. The TGFß-type I receptor kinase inhibitor GW788388 (1 µM) was used as a negative control. Pathway analysis revealed the induction of key stress-response pathways, including Nrf2 oxidative stress response, unfolding protein response, and metal stress response. Early response genes per pathway were identified much earlier than 24 h and included HMOX1, ATF3, DDIT3, and several MT1 isotypes. GW788388 did not induce any genes within the stress response pathways above, but showed deregulation of genes involved in TGFß inhibition, including downregulation of CYP24A1 and SERPINE1 and upregulation of WT1. This study highlights the application of iPSC-derived renal cells for prediction of cellular toxicity and sheds new light on the temporal and early effects of key genes that are involved in cellular stress response pathways.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Células Madre Pluripotentes Inducidas / Transcriptoma Idioma: En Revista: Cell Biol Toxicol Asunto de la revista: TOXICOLOGIA Año: 2023 Tipo del documento: Article País de afiliación: Países Bajos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Células Madre Pluripotentes Inducidas / Transcriptoma Idioma: En Revista: Cell Biol Toxicol Asunto de la revista: TOXICOLOGIA Año: 2023 Tipo del documento: Article País de afiliación: Países Bajos