Gadolinium and gadoteric acid single exposure – long-term impact on the kidney’s gene expression

Abstract

Background: In gadolinium-based contrast agents (GBCAs), gadolinium [Gd (III)] is chelated to prevent its toxicity. Gadoteric acid (Gd-DOTA), a macrocyclic GBCA with a more stable structure, is commonly used in magnetic resonance imaging [1]. The kidney is one of the major targets of Gd (III), since renal excretion is the main elimination route for most GBCAs [2]. In healthy rats exposed to a single dose of Gd (III) or Gd-DOTA, the kidney transcriptome, compared to controls, showed different gene expression patterns [3]. Objective: This study aims to evaluate the long-term effects of Gd (III) or Gd-DOTA single exposure on kidney gene expression. Methods: Male Wistar rats were divided into 3 groups (n=10 each) and exposed to a single dose (0.1 mmol/kg) of Gd (III), Gd-DOTA or vehicle (control); 20 weeks after exposure, renal tissue was collected to evaluate differential gene expression of its transcriptome (RNASeq), followed by Gene Set Enrichment Analysis (GSEA) of all the identified differentially expressed genes. Results: Compared to controls, the Gd (III) group showed an up-regulation of Ly6al (Lymphocyte Antigen 6 Complex, Locus A-like), Snap91 (Synaptosome Associated Protein 91) and Fosfb (FosB proto-oncogene, AP-1 transcription factor subunit) genes; and Gd-DOTA group showed an upregulation of Ly6al, Snap91 and Ugt2b7 (UDP-glucuronosyltransferase family 2 member B7) genes, and a down-regulation of Cyp26b1 (Cytochrome P450, family 26, subfamily b, polypeptide 1) gene. Gd-DOTA, compared to the Gd (III) group, showed an upregulation of Ly6al and Ugt2b7 genes, and downregulation of Cyp26b1 and Fosfb genes. GSEA analysis for Gd-DOTA showed values of reasonable enrichment (>2) in all the studied genes, while for Gd (III), only Cyp26b1 and Fosfb were altered. Conclusions: Single exposure to free Gd (III) or Gd-DOTA induced distinct transcriptional responses in the kidney, showing that Gd-DOTA had a unique profile of gene expression, compared to free Gd (III). Moreover, the GSEA results imply a possible alternative biological pathway(s) activation for each compound. Gd (III) or Gd-DOTA exposure induced long-term disturbances in the expression of genes associated with immunity and xenobiotic metabolism. Further confirmatory studies (qPCR assays) are necessary to validate our gene expression results, allowing the exploration of our data for new insights about Gd (III) impact on kidney function, and Gd-DOTA safety, as Fosfb appears to be involved in acute kidney injury [4].