{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T21:58:00Z","timestamp":1773352680169,"version":"3.50.1"},"reference-count":90,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2021,12,8]],"date-time":"2021-12-08T00:00:00Z","timestamp":1638921600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"FCT\u2014Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia"},{"name":"scope of the project","award":["UIDP\/04378\/2020"],"award-info":[{"award-number":["UIDP\/04378\/2020"]}]},{"name":"scope of the project","award":["UIDB\/04378\/2020"],"award-info":[{"award-number":["UIDB\/04378\/2020"]}]},{"name":"Research Unit on Applied Molecular Biosciences\u2014UCIBIO and the project","award":["LA\/P\/0140\/2020"],"award-info":[{"award-number":["LA\/P\/0140\/2020"]}]},{"name":"Associate Laboratory Institute for Health and Bioeconomy\u2014i4HB"},{"name":"FCT\/MCTES","award":["PTDC\/MEC-CAR\/31322\/2017"],"award-info":[{"award-number":["PTDC\/MEC-CAR\/31322\/2017"]}]},{"name":"FEDER\/COMPETE 2020","award":["POCI-01-0145-FEDER-031322"],"award-info":[{"award-number":["POCI-01-0145-FEDER-031322"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,2,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Mounting evidence on the short- and long-term adverse effects associated with gadolinium [Gd (III)]-based contrast agents used in magnetic resonance imaging have emerged in the past 3 decades. Safety issues arise from the release of Gd (III) from chelates and its deposition in tissues, which is exacerbated in patients with renal disease, because the kidney is the major excretion organ of most of these agents. This study aimed at unveiling the cellular and molecular mechanisms of nephrotoxicity of Gd (III), using an in vitro model of human proximal tubular cells (HK-2 cell line). Cell viability declined in a concentration- and time-dependent manner after exposure to GdCl3\u00b76H2O. The estimated inhibitory concentrations (ICs) eliciting 1%\u201350% of cell death, after 24\u2009h of exposure, ranged from 3.4 to 340.5\u2009\u00b5M. At toxic concentrations, exposure to Gd (III) led to disruption of the oxidative status, mitochondrial dysfunction, cell death by apoptosis, switching to necrosis at higher levels, and autophagic activation. Disturbance of the lipid metabolism was already observed at low-toxicity ICs, with accumulation of lipid droplets, and upregulation of genes related to both lipogenesis and lipolysis. Gd (III)-exposure, even at the subtoxic IC01, increased the expression of modulators of various signaling pathways involved in the development and progression of renal disease, including inflammation, hypoxia, and fibrosis. Our results give new insights into the mechanisms underlying the nephrotoxic potential of Gd (III) and highlight the need to further clarify the risks versus benefits of the Gd (III)-based contrast agents currently in use.<\/jats:p>","DOI":"10.1093\/toxsci\/kfab148","type":"journal-article","created":{"date-parts":[[2021,12,1]],"date-time":"2021-12-01T12:33:25Z","timestamp":1638362005000},"page":"134-148","source":"Crossref","is-referenced-by-count":7,"title":["Cellular and Molecular Pathways Underlying the Nephrotoxicity of Gadolinium"],"prefix":"10.1093","volume":"186","author":[{"given":"N\u00edcia","family":"Reis Sousa","sequence":"first","affiliation":[{"name":"TOXRUN\u2014Toxicology Research Unit, University Institute of Health Sciences, CESPU, CRL, Gandra PRD 4585-116, Portugal"},{"name":"Departamento de Ci\u00eancias e Tecnologia da Sa\u00fade, Instituto Superior Polit\u00e9cnico de Benguela, Benguela 1444, Angola"}]},{"given":"Susana","family":"Rocha","sequence":"additional","affiliation":[{"name":"LAQV, REQUIMTE, Laborat\u00f3rio de Qu\u00edmica Aplicada, Departamento de Ci\u00eancias Qu\u00edmicas, Faculdade de Farm\u00e1cia da Universidade do Porto, Porto 4050-313, Portugal"}]},{"given":"Alice","family":"Santos-Silva","sequence":"additional","affiliation":[{"name":"Associate Laboratory i4HB\u2014Institute for Health and Bioeconomy, Faculdade de Farm\u00e1cia da Universidade do Porto, Porto 4050-313, Portugal"},{"name":"UCIBIO\u2014Applied Molecular Biosciences Unit, Department of Biological Sciences, Faculdade de Farm\u00e1cia da Universidade do Porto, Porto 4050-313, Portugal"}]},{"given":"Susana","family":"Coimbra","sequence":"additional","affiliation":[{"name":"TOXRUN\u2014Toxicology Research Unit, University Institute of Health Sciences, CESPU, CRL, Gandra PRD 4585-116, Portugal"},{"name":"Associate Laboratory i4HB\u2014Institute for Health and Bioeconomy, Faculdade de Farm\u00e1cia da Universidade do Porto, Porto 4050-313, Portugal"},{"name":"UCIBIO\u2014Applied Molecular Biosciences Unit, Department of Biological Sciences, Faculdade de Farm\u00e1cia da Universidade do Porto, Porto 4050-313, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6162-2426","authenticated-orcid":false,"given":"Maria Jo\u00e3o","family":"Valente","sequence":"additional","affiliation":[{"name":"Associate Laboratory i4HB\u2014Institute for Health and Bioeconomy, Faculdade de Farm\u00e1cia da Universidade do Porto, Porto 4050-313, Portugal"},{"name":"UCIBIO\u2014Applied Molecular Biosciences Unit, Department of Biological Sciences, Faculdade de Farm\u00e1cia da Universidade do Porto, Porto 4050-313, Portugal"}]}],"member":"286","published-online":{"date-parts":[[2021,12,8]]},"reference":[{"key":"2022022809423074800_kfab148-B1","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1007\/s11604-019-00835-1","article-title":"Changes in tissue gadolinium biodistribution measured in an animal model exposed to four chelating agents","volume":"37","author":"Acar","year":"2019","journal-title":"Jpn. 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