Characterization of renal toxicity in mice administered the marine biotoxin domoic acid

Jason A. Funk, Michael G. Janech, Joshua C. Dillon, John Bissler, Brian J. Siroky, P. Darwin Bell

Research output: Contribution to journalArticle

13 Citations (Scopus)

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 consistentwith acute tubular necrosis, apoptosis, and renal tubular cell desquamation, with toxic vacuolization and mitochondrial swelling as hallmarks of the cellular damage. Doses≥0.1mg/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 toxicitymay require consideration when determining safe levels for human exposure.

Original languageEnglish (US)
Pages (from-to)1187-1197
Number of pages11
JournalJournal of the American Society of Nephrology
Volume25
Issue number6
DOIs
StatePublished - Jun 1 2014

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Kidney
domoic acid
Shellfish Poisoning
Mitochondrial Swelling
Kynurenic Acid
fos Genes
Ionotropic Glutamate Receptors
Diatoms
Excitatory Amino Acid Antagonists
Excitatory Amino Acids
Poisons
Wounds and Injuries
Glutamate Receptors
Nervous System
Blood Vessels
Glutamic Acid
Necrosis
Biomarkers
Apoptosis

All Science Journal Classification (ASJC) codes

  • Nephrology

Cite this

Characterization of renal toxicity in mice administered the marine biotoxin domoic acid. / Funk, Jason A.; Janech, Michael G.; Dillon, Joshua C.; Bissler, John; Siroky, Brian J.; Bell, P. Darwin.

In: Journal of the American Society of Nephrology, Vol. 25, No. 6, 01.06.2014, p. 1187-1197.

Research output: Contribution to journalArticle

Funk, Jason A. ; Janech, Michael G. ; Dillon, Joshua C. ; Bissler, John ; Siroky, Brian J. ; Bell, P. Darwin. / Characterization of renal toxicity in mice administered the marine biotoxin domoic acid. In: Journal of the American Society of Nephrology. 2014 ; Vol. 25, No. 6. pp. 1187-1197.
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