Differential expression of renal urate transporters in male and female mice

Elevated urate (UA) levels in the serum (hyperuricemia, HUA) can contribute to the development of many diseases, including kidney stones, chronic kidney disease, cardiovascular disease, metabolic syndrome, and gout, the most prevalent form of inflammatory arthritis. Men are 5‐fold more likely to have HUA than women, however, this risk increases in women 4‐fold 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 hyperuricemia mice models. Previously, we found insertion of the orthologous human pathological mutation Q141K (Q140K in mice) in the UA transporter ABCG2 causes significant hyperuricemia in the male mice but not in the female mice. Paradoxically, we also observed female mice have lower fractional UA excretion than males, suggesting complex differences in the renal handling between males and females. We hypothesized that these differences were likely due to either UA transporter expression or regulation. To better understand the gene expression architecture of UA transporters in the mouse kidney, we compared gene expression in male and female wild type (WT) and Q140K ABCG2 mice. RNA‐Seq was performed followed by DESeq2 analysis to determine differentially expressed genes between males and females of each genotype. Targets of interest included the 12 transporter and 3 transcription factor (TF) genes that associate 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 all the UA associated transporter genes, except ABCG2 and SLC2A9 . Specifically, female mice had lower transcript expression of UA transporters SLC22A12 , SLC22A6 , SLC17A1 , and ABCA1 . These genes have variants that associated with lower UA levels in human populations, consistent with the female mice potentially more efficiently excreting surplus UA. Females also had significantly lower levels of the 3 key urate associated transcription factors HNF1A, HNF4A, and HNF4G, providing a potential mechanism of differentiation. Interestingly, the Q140K mice DESeq2 analysis reveals 486 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. These findings strongly suggest female sex may confer protection from developing HUA and associated conditions. Further understanding this mechanism should lead to improved understanding of UA homeostasis and new insights into HUA treatment. Support or Funding Information NIDDK R01DK114091