Abstract: TH-PO254

Sex Differences in Renal Toxicity of the Neurotoxin Domoic Acid

Session Information

Category: Acute Kidney Injury

  • 001 AKI: Basic

Authors

  • Thompson, Robert Griffin, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Grenett, Hernan E, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • He, Lan, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Bell, P. Darwin, University of Alabama at Birmingham , Birmingham, Alabama, United States
Background

The algae-derived neurotoxin, domoic acid (DA), is an ionotropic receptor agonist and is currently considered an increasing threat to mammals and other species. Intraperitoneal administration (IP) of 4-5 mg/Kg/BW in mice has been found to cause neurological symptoms\damage. However, we recently reported (Funk, JASN 2014) that the kidney was 100 times more susceptible to injury with DA compared to brain. With IP injection, the kidney has a 4-fold higher concentration of DA compared to brain and prior probenecid treatment leads to even greater accumulations of DA, suggesting that DA is both filtered andis secreted by the kidney. Organic Anion Transporters such as OAT-1, OAT-2, and OAT-3 participate in helping mediate drug and toxin removal by the kidney through the process of secretion. In epithelial tissues, OAT-1 and OAT-3 are located at the basolateral membrane, and OAT-2 is located at the apical membrane (Nigam SK, Physiological Review 2015). The purpose of these studies was to determine if there is a gender sex difference in the renal injury response to DA.

Methods

Doses of 0.05 mg/Kg and 0.005 mg/Kg were IP injected into C57BL6 mice and 30 mins later the early injury-response genes c-fos, Junb, and EGR-1 were quantified using RT-qPCR. RT-qPCR was also performed to assess the mRNA levels for organic anion transporters in both male and female mice at 0.05mg/Kg DA.

Results

After 30 minutes both male and female mice exhibited an increase in gene expression. Surprisingly, female mice expression of early response genes was significantly higher compared to male mice. OAT-1, OAT-2, and OAT-3 in males were slightly upregulated; however, female mice showed no change in mRNA expression for OAT-1, OAT-2, and OAT-3.

Conclusion

These results demonstrate that female mice are more susceptible to renal injury compared to male mice in response to very low doses of DA. This difference may be due to a reduced ability for the renal secretion of DA though organic anion transport pathways.

Funding

  • Other NIH Support