Project Summary
Hyperuricemia, or elevated serum uric acid, is estimated to effect 20 – 25% of the
general population, but only 4 – 6% of pre-menopausal women. Hyperuricemia causes kidney
stones and gout, and also is an independent risk factor for chronic kidney disease,
cardiovascular disease, hypertension, and metabolic syndrome. Uric acid (UA) excretion is
mediated by the kidney (70%) and the gut (30%) and is a complicated balance of reabsorption
and secretion. A single nucleotide polymorphism in the gene encoding the primary UA secretory
transporter, ABCG2 Q141K, is both a hyperuricemia and gout risk variant, and associates with
sex differences in serum uric acid (SUA) levels. The pathophysiology of hyperuricemia and the
regulation of ABCG2 and other UA transporters are, however, poorly understood, especially in
women. In our recent genome wide association study, we found that two transcription factors,
HNF1A and HNF4A, associate with SUA levels and that these transcription factors may directly
regulate uric acid transporters like ABCG2. How these transcription factors are influenced by
uric acid, and how they may be differentially regulated in women are also unknown. Our
preliminary data suggests that UA is acting as a signaling molecule, triggering various kinase
cascades that activate transcription of UA transporters. We will explore this hypothesis by first
determining if UA levels regulate the important transcription factors HNF1A and HNF4A invitro.
Next, we will determine if hyperuricemia regulates transporter transcription factor abundance or
activity in our novel hyperuricemia mouse models. Finally, we will explore differential expression
of UA transporters in kidneys of male and female mice, and how regulation of these transporters
is sex specific. Understanding these mechanisms could lead to better treatment of
hyperuricemia to improve patient quality of life and decrease risk of developing associated co-
morbidities, such as cardiovascular, metabolic, and kidney diseases.