Renal toxicity of domoic acid

Domoic acid (DA) is a glutamate analog and a characterized neurotoxicant. Outside of the CNS, glutamate receptors are also found in peripheral tissues, including the kidney, which opens the possibility that the kidney may also be susceptible to excitatory toxicity. When mice were injected with DA (2.5 mg/kg, i.p.), and euthanized between 30 min and 2 hr after injection, DA concentrations were approximately four‐fold higher in the kidney than any other tissue examined. Probenecid co‐administration (600 mg/kg) further augmented concentrations in the serum, kidney, heart and hippocampus, highlighting organic anion transporters in the renal clearance of DA. To determine nephrotoxicity, mice were injected with DA (0.25–2.5 mg/kg), a range below that which elicits overt neurotoxic effects, for three consecutive days. No change in serum creatinine was observed; however, urinary NGAL was elevated within 24 hr, and urinary kidney injury molecule‐1 (uKim‐1) was elevated 72 hr after initial dose. Tissue analysis also showed elevated NGAL and Kim‐1 protein in the kidneys of mice exposed to DA. Additionally, fluorescent imaging revealed alterations in aquaporin‐2 and Na + ,K + ‐ATPase localization in medullary collecting ducts. Finally, when DA was administered after a 12 hr dehydration period, uKim‐1 was increased compared to DA alone, suggesting water restriction exacerbated kidney injury. Overall the data indicate that DA is preferentially distributed to the kidneys, clearance is dependent upon organic anion transport, and renal toxicity occurs within a concentration range below what is known to elicit neurotoxicity. JAF is supported by the training grant 5T32DK007752–14 (NIDDK/NIH).