Gadoteric acid and gadolinium exposure – what is the impact on kidney gene expression?

Abstract

Background: The nephrotoxicity of gadolinium [Gd (III)] has been reported, raising concerns about the safety of gadolinium-based contrast agents (GBCA). Gd (III) exposure, in renal tubular cells (HK-2), causes apoptosis, and leads to upregulation of genes related to lipogenesis/lipolysis and to signaling pathways related to inflammation/hypoxia [1].Gadoteric acid (Gd-DOTA), a macrocyclic GBCA, appears to be one of the more stable. Recently, we reported that, in healthy rats exposed to a single dose of Gd (III) or Gd-DOTA, the kidneys’ transcriptome, compared to controls, presented distinct differential gene expression patterns [2]. Objective: To evaluate the short- and long-term effects of exposure to Gd (III) and Gd-DOTA on the kidney’s gene expression of genes specifically related to apoptosis, inflammation, hypoxia and lipid metabolism. Methods: In short- and long-term studies (2 days and 20 weeks after exposure, respectively), male Wistar rats were divided in 3 groups/study (n=10/group) and exposed to a single dose (0.1 mmol/kg) of Gd (III), Gd-DOTA or vehicle (control). At the end of the protocols, renal tissue was collected to evaluate the kidney gene expression of casp3, bcl2, spp1, sqstm1, nfkb1, nfe2, nlrp3, il6, tgfb1, il1b, hif1a, acaca and cpt1a, through qPCR. Results: Two days after exposure, Gd (III) group presented higher levels of gene expression of il6, tgbf1, nfkb1 and hif1a than the controls and, compared to Gd-DOTA group, tgbf1 and acaca mRNA levels were increased; the Gd-DOTA group presented increased levels of il6 and cpt1a, compared to the control group. Twenty weeks after exposure, Gd (III) group presented decreased gene expression of tgbf1 and acaca compared to the controls; the Gd-DOTA group presented lower tgbf1 mRNA levels than the control group. Conclusions: Short-term exposure to free Gd (III) was associated with upregulation of genes related to hypoxia and inflammation, while exposure to Gd-DOTA was only associated with upregulation of il6 (encoding interleukin-6) and cpt1a, which encodes for carnitine palmitoyltransferase 1A, an enzyme involved in fatty acid oxidation. Over time, these alterations seem to reduce or even revert for both compounds, since in the long term, only gene expression downregulation was observed. Gd-DOTA revealed a safer profile, however, further studies are warranted to evaluate its true safety, especially in cases of repeated exposures and/or pre-existing renal function impairment.