Uncovering sex differences in uric acid handling

项目总结

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.