title: Characterization of renal toxicity in mice administered the marine biotoxin domoic Acid.
abstract: Domoic acid (DA), an excitatory amino acid produced by diatoms belonging to the genus Pseudo-nitzschia, is a glutamate analog responsible for the neurologic condition referred to as amnesic shellfish poisoning. To date, the renal effects of DA have been underappreciated, although renal filtration is the primary route of systemic elimination and the kidney expresses ionotropic glutamate receptors. To characterize the renal effects of DA, we administered either a neurotoxic dose of DA or doses below the recognized limit of toxicity to adult Sv128/Black Swiss mice. DA preferentially accumulated in the kidney and elicited marked renal vascular and tubular damage consistent with acute tubular necrosis, apoptosis, and renal tubular cell desquamation, with toxic vacuolization and mitochondrial swelling as hallmarks of the cellular damage. Doses≥0.1 mg/kg DA elevated the renal injury biomarkers kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin, and doses≥0.005 mg/kg induced the early response genes c-fos and junb. Coadministration of DA with the broad spectrum excitatory amino acid antagonist kynurenic acid inhibited induction of c-fos, junb, and neutrophil gelatinase-associated lipocalin. These findings suggest that the kidney may be susceptible to excitotoxic agonists, and renal effects should be considered when examining glutamate receptor activation. Additionally, these results indicate that DA is a potent nephrotoxicant, and potential renal toxicity may require consideration when determining safe levels for human exposure.
authors: Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina;
authors: Jason A
authors: JA
authors: Funk
authors: Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina;
authors: Michael G
authors: MG
authors: Janech
authors: Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina;
authors: Joshua C
authors: JC
authors: Dillon
authors: Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; and.
authors: John J
authors: JJ
authors: Bissler
authors: Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; and.
authors: Brian J
authors: BJ
authors: Siroky
authors: Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina; Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina bellpd@musc.edu.
authors: P Darwin
authors: PD
authors: Bell
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007608:Kainic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008387:Marine Toxins / Q000493:pharmacokinetics / Q000633:toxicity*; D008815:Mice, Inbred Strains; D046529:Microscopy, Electron, Transmission; D008933:Mitochondrial Swelling / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009467:Neuromuscular Depolarizing Agents / Q000493:pharmacokinetics / Q000633:toxicity*; D009469:Neuromuscular Junction / Q000187:drug effects* / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D018092:Kainic Acid Receptors / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014617:Vacuoles / Q000473:pathology / Q000648:ultrastructure; D000097806:GluK2 Kainate Receptor
chemical_list: D007608:Kainic Acid; D008387:Marine Toxins; D009467:Neuromuscular Depolarizing Agents; D016760:Proto-Oncogene Proteins c-fos; D018092:Kainic Acid Receptors; D014157:Transcription Factors; D000097806:GluK2 Kainate Receptor; C584097:JunB protein, mouse; C012301:domoic acid