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Abstract: PO1408

Sex Differences in Expression of Renal Urate Transporters

Session Information

Category: Fluid, Electrolyte, and Acid-Base Disorders

  • 901 Fluid, Electrolyte, and Acid-Base Disorders: Basic

Authors

  • Halperin Kuhns, Victoria L., University of Maryland School of Medicine, Baltimore, Maryland, United States
  • Woodward, Owen M., University of Maryland School of Medicine, Baltimore, Maryland, United States
Background

Elevated urate (UA) levels in the serum (hyperuricemia, HUA) can contribute to the development of diseases, including kidney stones, chronic kidney disease, cardiovascular disease, metabolic syndrome, and gout. Men are 5x more likely to have HUA than women, yet this risk increases in women 4x after menopause. This suggests premenopausal women are protected against developing HUA, but the mechanisms have yet to be elucidated. These differences are echoed in our HUA mouse model, where insertion of an orthologous human pathological UA transporter ABCG2 variant Q141K (Q140K in mice) causes significant HUA in the male but not female mice. Paradoxically, we found female mice had lower fractional UA excretion than males, suggesting complex differences in the renal UA handling between the sexes. We hypothesized that these differences were likely due to either UA transporter expression or regulation.

Methods

RNA-Seq was performed on male and female wild type (WT) and Q140K mice, followed by DESeq2 analysis to determine differentially expressed genes between both sexes of each genotype.

Results

Targets of interest included 12 transporter and 3 transcription factor (TF) genes that associated with serum UA levels in humans in recent genome wide association studies. We found small (0.49–2.1-fold) but statistically significant changes in many of these transporter genes. Specifically, female mice had lower expression of UA transporters SLC22A12, SLC22A6, SLC17A1,SLC17A3, and ABCA1. These genes have variants that associated with lower UA levels in human populations, consistent with female mice potentially more efficiently excreting surplus UA. Females also had significantly lower levels of the 3 key UA associated TFs, HNF1A, HNF4A, and HNF4G, providing a possible mechanism of differentiation. The Q140K mice DESeq2 analysis reveals 273 alterations in male Q140K kidney gene expression as compared to WT, including 5 potentially compensatory SLC transporters. None of these changes were observed in female Q140K mice, indicating that changes are the result of the elevation in SUA and not due to mutant ABCG2 protein.

Conclusion

Female sex may confer protection from developing HUA and related conditions. Further understanding this mechanism should lead to improved understanding of UA homeostasis and new insights into HUA treatment.

Funding

  • NIDDK Support