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

DOI record: { "DOI": "10.1007/s00204-022-03306-1", "ISSN": [ "0340-5761", "1432-0738" ], "URL": "http://dx.doi.org/10.1007/s00204-022-03306-1", "abstract": "<jats:title>Abstract</jats:title><jats:p>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 (<jats:italic>C</jats:italic><jats:sub>max</jats:sub> 9 µM) using H9c2 rat cardiomyoblasts, neonatal mouse cardiomyocytes (NMCM), rat NRK-52E and human RPTEC/TERT1 cells as cell models for the assessment of cardiotoxicity or nephrotoxicity, respectively. Due to the known potential of nucleoside analogs for the induction of mitochondrial toxicity, we assessed mitochondrial function in response to remdesivir treatment, early proteomic changes in NMCM and RPTEC/TERT1 cells and the contractile function of NMCM. Short-term treatments (24 h) of H9c2 and NRK-52E cells with remdesivir adversely affected cell viability by inhibition of proliferation as determined by significantly decreased <jats:sup>3</jats:sup>H-thymidine uptake. Mitochondrial toxicity of remdesivir (1.6–3.1 µM) in cardiac cells was evident by a significant decrease in oxygen consumption, a collapse of mitochondrial membrane potential and an increase in lactate secretion after a 24–48-h treatment. This was supported by early proteomic changes of respiratory chain proteins and intermediate filaments that are typically involved in mitochondrial reorganization. Functionally, an impedance-based analysis showed that remdesivir (6.25 µM) affected the beat rate and contractility of NMCM. In conclusion, we identified adverse effects of remdesivir in cardiac and kidney cells at clinically relevant concentrations, suggesting a careful evaluation of therapeutic use in patients at risk for cardiovascular or kidney disease.</jats:p>", "alternative-id": [ "3306" ], "assertion": [ { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "Received", "name": "received", "order": 1, "value": "9 December 2021" }, { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "Accepted", "name": "accepted", "order": 2, "value": "27 April 2022" }, { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "First Online", "name": "first_online", "order": 3, "value": "17 May 2022" }, { "group": { "label": "Declarations", "name": "EthicsHeading" }, "name": "Ethics", "order": 1 }, { "group": { "label": "Conflict of interest", "name": "EthicsHeading" }, "name": "Ethics", "order": 2, "value": "The authors have no relevant financial or non-financial interests to disclose." } ], "author": [ { "ORCID": "https://orcid.org/0000-0002-3411-8686", "affiliation": [], "authenticated-orcid": false, "family": "Merches", "given": "Katja", "sequence": "first" }, { "affiliation": [], "family": "Breunig", "given": "Leonie", "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0003-3781-6532", "affiliation": [], "authenticated-orcid": false, "family": "Fender", "given": "Julia", "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0002-0630-4537", "affiliation": [], "authenticated-orcid": false, "family": "Brand", "given": "Theresa", "sequence": "additional" }, { "affiliation": [], "family": "Bätz", "given": "Vanessa", "sequence": "additional" }, { "affiliation": [], "family": "Idel", "given": "Svenja", "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0002-2673-0488", "affiliation": [], "authenticated-orcid": false, "family": "Kollipara", "given": "Laxmikanth", "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0003-1441-6149", "affiliation": [], "authenticated-orcid": false, "family": "Reinders", "given": "Yvonne", "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0002-2388-5265", "affiliation": [], "authenticated-orcid": false, "family": "Sickmann", "given": "Albert", "sequence": "additional" }, { "affiliation": [], "family": "Mally", "given": "Angela", "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0002-5747-2207", "affiliation": [], "authenticated-orcid": false, "family": "Lorenz", "given": "Kristina", "sequence": "additional" } ], "container-title": "Archives of Toxicology", "container-title-short": "Arch Toxicol", "content-domain": { "crossmark-restriction": false, "domain": [ "link.springer.com" ] }, "created": { "date-parts": [ [ 2022, 5, 17 ] ], "date-time": "2022-05-17T08:03:34Z", "timestamp": 1652774614000 }, "deposited": { "date-parts": [ [ 2022, 6, 22 ] ], "date-time": "2022-06-22T12:03:03Z", "timestamp": 1655899383000 }, "funder": [ { "DOI": "10.13039/501100002347", "award": [ "ERKCasting: 16GW0262K" ], "award-info": [ { "award-number": [ "ERKCasting: 16GW0262K" ] } ], "doi-asserted-by": "publisher", "id": [ { "asserted-by": "publisher", "id": "10.13039/501100002347", "id-type": "DOI" } ], "name": "Bundesministerium für Bildung und Forschung" }, { "DOI": "10.13039/501100002347", "award": [ "ChInValue: 03INT703AB" ], "award-info": [ { "award-number": [ "ChInValue: 03INT703AB" ] } ], "doi-asserted-by": "publisher", "id": [ { "asserted-by": "publisher", "id": "10.13039/501100002347", "id-type": "DOI" } ], "name": "Bundesministerium für Bildung und Forschung" }, { "DOI": "10.13039/501100001659", "award": [ "SFB/TR296" ], "award-info": [ { "award-number": [ "SFB/TR296" ] } ], "doi-asserted-by": "publisher", "id": [ { "asserted-by": "publisher", "id": "10.13039/501100001659", "id-type": "DOI" } ], "name": "Deutsche Forschungsgemeinschaft" }, { "DOI": "10.13039/501100001659", "award": [ "SFB 1525" ], "award-info": [ { "award-number": [ "SFB 1525" ] } ], "doi-asserted-by": "crossref", "id": [ { "asserted-by": "crossref", "id": "10.13039/501100001659", "id-type": "DOI" } ], "name": "Deutsche Forschungsgemeinschaft" }, { "name": "Drug Discovery Hub Dortmund" }, { "DOI": "10.13039/501100009379", "award": [ "E-A-431" ], "award-info": [ { "award-number": [ "E-A-431" ] } ], "doi-asserted-by": "publisher", "id": [ { "asserted-by": "publisher", "id": "10.13039/501100009379", "id-type": "DOI" } ], "name": "Interdisziplinäres Zentrum für Klinische Forschung, Universitätsklinikum Würzburg" }, { "DOI": "10.13039/501100008848", "doi-asserted-by": "publisher", "id": [ { "asserted-by": "publisher", "id": "10.13039/501100008848", "id-type": "DOI" } ], "name": "Elitenetzwerk Bayern" }, { "name": "Leibniz-Institut für Analytische Wissenschaften - 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