A sugar transporter regulates serum urate levels: Implications for prevention and management of hyperuricemia in gout

Abstract

Introduction: Gout is increasing in prevalence in the United States. More patients with refractory tophaceous disease are being seen, including older patients and those with multiple comorbidities such as diabetes, hypertension, chronic kidney disease, and congestive heart failure. There is also growing but as yet unresolved evidence for the potential of hyperuricemia to directly impact on blood pressure and cardiovascular diseases. New treatments, such as febuxostat and pegloticase, are emerging for refractory hyperuricemia. However, in most gout patients hyperuricemia is caused by long-standing renal underexcretion of uric acid, an abnormality that is often precipitated or exacerbated by diuretic therapy, insulin resistance, hypertension, and development of even moderate degrees of renal insuffi ciency [1]. This scenario points to opportunities to intervene at the level of both prophylaxis and treatment of hyperuricemia by more advanced uricosuric therapies. This will be aided by recent clinical-translational advances in understanding renal uric acid disposition. The primary uricosuric drugs (probenecid, benzbromarone, sulfi npyrazone) and the weaker secondary uricosuric drug (losartan) work in large part by inhibiting the urate anion exchanger URAT1 (SLC22A12) at the apical (brush border) membrane of the renal proximal tubule epithelial cell [2]. Furthermore, several URAT1 single nucleotide polymorphisms (SNPs) were linked with prominent regulatory effects on serum urate and susceptibility to gout in Asian and European cohorts [2]. Although URAT1 appears to be the linchpin for urate reabsorption at the apical surface of the renal proximal tubule epithelial cell, URAT1 knockout mice showed an unexpectedly small loss in renal urate reabsorption [3]. Secondary changes in renal urate secretion were believed to be partly responsible. SLC2A9 (also known as GLUT9, URATv1) promotes transport of hexose sugars and is a potent electrogenic transporter of urate anion [4]. Recently, probenecid and benzbromarone (and also indomethacin) were discovered to inhibit the activity of SLC2A9 at the basolateral membrane of the proximal renal tubule epithelial cell [4], the interface where urate is reabsorbed into the peritubular interstitium and ultimately back into the venous circulation. Not only URAT1, but also SLC2A9 mutations, have now been implicated in the etiology of the uncommon disorder idiopathic renal hypouricemia. Furthermore, SLC2A9 mutations were linked to hyperuricemia and bladder uric acid calculi in dalmatian-breed dogs [5]. This was a stunning observation that indicates how robust the role for SLC2A9 can be in renal urate handling, as dogs, like other lower mammals, are generally protected from hyperuricemia via uricase expression. More recently, several SLC2A9 SNPs have been linked by genome-wide association (GWA) studies with hyperuricemia, altered renal uric handling, and susceptibility to gout [6–9].