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Abstract: SA-PO077

Identifying the Cellular and Molecular Mechanisms That Contribute to Gadolinium-Based Contrast Agent-Induced Nephrotoxicity

Session Information

  • AKI: Mechanisms - III
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Deaguero, Joshua, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States
  • Dokladny, Karol, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States
  • Escobar, G. Patricia, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States
  • Wagner, Brent, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States

Group or Team Name

  • Kidney Institute of New Mexico
Background

Gadolinium (Gd3+) chelates are a dynamic tool used for enhancing magnetic resonance imaging (MRI) examinations. Owing to the vital clinical diagnostic capabilities of Gd3+, hundreds of millions gadolinium-based contrast agent doses have been administered worldwide. Long-term tissue retention of gadolinium and nephrogenic systemic fibrosis are well correlated with exposures to these contrast agents. The kidney is the major organ of excretion for most gadolinium-based contrast agents. This study aimed at identifying cellular and molecular perturbations as a result of gadolinium chelate exposure in an in vitro model of mouse renal tubular epithelial cells.

Methods

Mouse renal tubular epithelial cells (MRTEpiCs) were cultured at density of 25,000 cells/cm2 and allowed to reach 70-80% confluence prior to exposure. For the identification of perturbatory effects, cells were exposed to physiological concentrations (0.002 mM-2 mM) of Omniscan or Dotarem for 24h. Intracellular reactive oxygen species was measured using a fluorescent (DCFH-DA) assay. Mitochondrial and lysosomal activity was monitored using fluorescent probes and confocal microscopy.

Results

After 24h exposure both Omniscan and Dotarem induced a dose response effect on the increased generation of reactive oxygen species. Mitochondrial membrane potential decreased in response to agent exposure. Omniscan and Dotarem promoted the accumulation of lysosomes, as well as increased lysosomal-associated membrane protein 1 (LAMP1) protein expression.

Conclusion

In this study we identify potential cellular and molecular modulators involved in the observed nephrotoxicity of gadolinium-based contrast agents. We demonstrate that gadolinium chelates induces mitochondrial dysfunction and increased lysosomal activity indicating an impact on organelle dynamics. These data can be used to enhance preclinical safety studies by improving assay sensitivities.

Cellular perturbations induced by GBCAs.

Funding

  • NIDDK Support