Dataset Information

The potential of remdesivir to affect function, metabolism and proliferation of in vitro heart and kidney models

ABSTRACT: Here, we performed an in vitro toxicity assessment for remdesivir at clinically relevant concentrations around the cmax of 9 µM using H9c2 rat cardiomyoblasts and neonatal mouse cardiomyocytes (NMCM) as heart models and rat NRK-52E cells and human RPTEC/TERT1 cells as kidney models. Due to the tendency of nucleoside analogs for mitochondrial toxicity, we focused on metabolic changes and mitochondrial function. Additionally, we analyzed the functionality of NMCM and determined early proteomic changes.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): Epithelial Cell, Fetal Cardiomyocyte

DISEASE(S): Cardiovascular System Disease

SUBMITTER: Laxmikanth Kollipara

LAB HEAD: Prof. Dr. Albert Sickmann

PROVIDER: PXD029311 | Pride | 2022-05-24

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	LK_SFB1116_NMCM_REMDESIVIR_LFQ.pep.xml	Pepxml
	RPTEC_REMDESIVIR_LFQ.pep.xml	Pepxml
	checksum.txt	Txt
	qExHF01_13955_RPTEC_DMSO.raw	Raw
	qExHF01_13956_RPTEC_REMDESIVIR.raw	Raw

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Publications

The potential of remdesivir to affect function, metabolism and proliferation of cardiac and kidney cells in vitro.

Merches Katja K Breunig Leonie L Fender Julia J Brand Theresa T Bätz Vanessa V Idel Svenja S Kollipara Laxmikanth L Reinders Yvonne Y Sickmann Albert A Mally Angela A Lorenz Kristina K

Archives of toxicology 20220517 8

Remdesivir is a prodrug of a nucleoside analog and the first antiviral therapeutic approved for coronavirus disease. Recent cardiac safety concerns and reports on remdesivir-related acute kidney injury call for a better characterization of remdesivir toxicity and understanding of the underlying mechanisms. Here, we performed an in vitro toxicity assessment of remdesivir around clinically relevant concentrations (C<sub>max</sub> 9 µM) using H9c2 rat cardiomyoblasts, neonatal mouse cardiomyocytes ...[more]

PMID: 35579693

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Project description:Toxicity testing is vital to protect human health from exposure to toxic chemicals in the environment. Furthermore, combining novel cellular models with molecular profiling technologies, such as metabolomics can add new insight into the molecular basis of toxicity and provide a rich source of biomarkers that are urgently required in a 21st Century approach to toxicology. We have used an NMR-based metabolic profiling approach to characterise for the first time the metabolome of the RPTEC/TERT1 cell line, an immortalised non-tumour human renal epithelial cell line that recapitulates phenotypic characteristics that are absent in other in vitro renal cell models. RPTEC/TERT1 cells were cultured with either the dosing vehicle (DMSO) or with exposure to one of six compounds (nifedipine, potassium bromate, monuron, D-mannitol, ochratoxin A and sodium diclofenac), several of which are known to cause renal effects. Aqueous intracellular and culture media metabolites were profiled by 1H NMR spectroscopy at 6, 24 and 72 hours of exposure to a low effect dose (IC10). We defined the metabolome of the RPTEC/TERT1 cell line and used a principal component analysis approach to derive a panel of key metabolites, which were altered by chemical exposure. By considering only major changes (+/- 1.5 fold change from control) across this metabolite panel we were able to show specific alterations to cellular processes associated with chemical treatment. Our findings suggest that metabolic profiling of RPTEC/TERT1 cells can report on the effect of chemical exposure on multiple cellular pathways at low-level exposure, producing different response profiles for the different compounds tested with a greater number of major metabolic effects observed in the toxin treated cells. Importantly, compounds with established links to chronic renal toxicity produced more diverse and severe perturbations to the cellular metabolome than non-toxic compounds in this model. As these changes can be rationalised with the different pharmacological and toxicity profiles of the chemicals it is suggested that metabolic profiling in the RPTEC/TERT1 model would be useful in investigating the mechanism of action of toxins at a low dose.

Project description:Drugs and other xenobiotics are not only secreted/reabsorbed by the renal proximal tubule epithelial cells (RPTEC) but may also adversely impact kidney function. In vitro models that can afford prediction of toxic effects and model directional transport are in high demand in both drug and chemical safety; accordingly, active development of new models is underway. The objective of this study was to investigate physiological and transport function of various sources of human RPTECs under static and fluidic conditions. We tested TERT1-immortalized RPTECs, including OAT1-, OCT2- and OAT3-overexpressing variants) and two primary RPETC sources. Cells were cultured on transwell membranes in two conditions – static (24-well transwells) and fluidic (transwells placed into PhysioMimix TC12 organ-on-chip platform with 2 L/s flow). We evaluated barrier formation, transport, and gene expression. We show that primary RPTECs may not be suitable for studies of directional transport on transwell membranes because they form an inferior barrier even though they show generally more relevant expression of key transporters, especially when shear stress is present. Both TERT1 and -OAT1 and -OAT3 overexpressing cells formed robust barrier, but it was unaffected by shear stress. TERT1-OAT1 cells exhibited inhibitable pAH transport; shear stress increased pAH transport function of these cells. However, efficient tenofovir secretion and perfluorooctanoic acid (PFOA) reabsorption by TERT1-OAT1 cells were not modulated by shear stress. With respect to gene expression profiles, we found that both TERT1 and TERT1-OAT1 cells exhibited human kidney-like transcriptomes, but that shear stress did not result in an apparent enhancement of the kidney phenotype. Overall, our data show that addition of flow to in vitro studies of the renal proximal tubule may afford benefits in some aspects of kidney function, but that careful consideration of the impact such studies would have on the cost and throughput of the experiments is needed.