Uric acid (UA) is a terminal metabolite of the purine metabolic pathway in humans. Excess UA, the clinical disorder hyperuricemia, affects 43 million Americans causing gout and increasing risk for hypertension, stroke, metabolic syndrome, and chronic kidney disease. A genetic and physiological approach led to our identification of the multidrug transporter ABCG2 as a high capacity UA efflux transporter and that common ABCG2 variants make the largest genetic contribution to increased UA levels and gout risk. Although the genetic role of ABCG2 in hyperuricemia and gout risk is now well established, we know little of the physiological role of ABCG2 as a renal UA transporter. The process of UA homeostasis is by necessity a dynamic process as diet and metabolism produce highly variable UA loads. Thus, the overarching goal of this proposal is to develop a mechanistic explanation of how ABCG2 mediated renal UA excretion is physiologically regulated, and how dysfunction of the process leads to hyperuricemia and human disease.
The AIMs of our proposal will address the following three questions: 1) Is ABCG2 physiologically regulated in vivo and a critical component of UA homeostasis? 2) What role does phosphorylation play in regulating ABCG2 and renal UA excretion? and 3) How does the common ABCG2 gout mutation Q141K alter ABCG2 regulation and the physiology of renal UA excretion? This work will provide a new understanding of the molecular mechanisms of urate homeostasis and illuminate both the consequences of dysregulated hyperuricemia on human health, and novel therapeutic targets for treatment.
High uric acid (hyperuricemia) causes gout and is a risk factor for hypertension and a number of metabolic diseases, yet we know little of how uric acid excretion is physiologically regulated. This proposal, using new animal models of hyperuricemia, will study how the prominent uric acid secretory transporter ABCG2 is regulated normally in the kidney or dysregulated in disease. This work will provide a new understanding of the molecular mechanisms of urate homeostasis and illuminate both the consequences of dysregulated hyperuricemia on human health and novel therapeutic targets for treatment.
|Tin, Adrienne; Li, Yong; Brody, Jennifer A et al. (2018) Large-scale whole-exome sequencing association studies identify rare functional variants influencing serum urate levels. Nat Commun 9:4228|