Gout - New Insights into a Forgotten Disease

Gout is a common metabolic disorder resulting from sodium urate crystal deposits in articular, cartilaginous, and soft tissues resulting in polyarthritis and kidney disease. Broad allopurinol and benzbromarone application has commonly been used as treatment, dramatically improving the clinical course in patients with hyperuricemia and gout. Adverse drug effects and unsatisfactory efficacy have rarely been observed. Increasing effectiveness of drug therapy was followed by a considerable decrease in scientific interest in the pathogenetic origins of hyperuricemia and gout.

An association between human Urate Transporter 1 (hURAT) and reduced renal uric acid excretion and hyperuricemia has recently been reported [1]. This was the first study to demonstrate that genetic variations in renal tubular transport proteins might result in decreased urate excretion accompanied by increased serum uric acid levels. The identification of new urate-transporting proteins and increasing numbers of patients with allopurinol hypersensitivity, in particular patients with acute tumor lysis syndrome, revived scientific efforts towards elucidating the molecular basis of uric acid homeostasis.

A significant reduction in renal uric acid clearance has been demonstrated in more than 90 % of all patients with hyperuricemia. Glomerular filtration and bidirectional urate transport, including both tubular secretion and reabsorption, are the essential physiological processes in renal uric acid handling [2]. Under normal conditions, uric acid is freely filtered in the glomeruli and almost completely reabsorbed from urine in the proximal tubule. Net urate excretion is determined by tubular urate secretion and post-secretory urate reabsorption. Several proteins involved in urate secretion have been identified over the last few years. Uric acid uptake from the interstitium is mediated by organic anion transporters (OATs), presumably OAT1 and OAT3, which are located in the basolateral membrane. Additionally, two proteins have been implicated in urate efflux from proximal tubule cells into the tubular lumen. Recently, van Aubel et al. [3] identified human multidrug resistance protein 4 (MRP4) as a renal apical organic anion efflux transporter that mediates an ATP-dependent urate transport through multiple allosteric binding sites. Furthermore, based on studies with human proximal tubule apical membrane vesicles, a voltage-dependent urate channel/antiporter (UAT) seems to be participate in urate efflux [4]. Human galectin-9, which shows a high homology to the rat urate transporter rUAT, has been proposed for the human urate channel/transporter hUAT [5] [6]. However, no association between proteins involved in tubular urate secretion and reduced uric acid excretion could be established, despite considerable efforts.

In humans, serum uric acid levels appear to be regulated mainly by urate reabsorption in the proximal tubule [7]. Urate/anion antiporter in human kidney turned out to be a member of the organic anion transporter family (SLC22A12) and was designated as human urate transporter 1 (hURAT1) [8]. Human URAT1 was exclusively expressed in the kidney and has been localized to the apical membrane of the proximal tubule [8]. Interestingly, testosterone doubled hURAT1 promoter activity, suggesting that hormonal regulation of hURAT1 is the root cause of observed differences in urate levels between males and females [9]. The crucial role of hURAT1 in renal urate reabsorption was confirmed by the finding that individuals with loss-of-function mutations in hURAT1 gene have dramatically increased uric acid excretion and develop idiopathic renal hypouricemia [8] [10]. On the other hand, a study on a German Caucasian population demonstrated that polymorphisms in the N-terminal of the hURAT1 gene were strongly associated with fractional uric acid excretion and serum uric acid level [1]. Although there are no experimental data available to date, alternative splicing, increased transcriptional activity, and protein-protein interactions are of potential importance in the enhanced urate reabsorption by hURAT1.

The improved understanding of the molecular basis of renal urate transport does not exclude the possibility that other genes modifying uric acid homeostasis may be involved in the pathogenesis of gout. An interesting hint has been provided by an association of the 825T-allele of G protein β3 subunit (GNB3) with higher serum uric level in healthy subjects [11]. Prior studies have shown that this polymorphism could also be associated with hypertension and lipolysis in human adipose cells [12] [13]. Obviously, there are multiple pathogenetic links between hyperuricemia and metabolic syndrome-related disorders.

Future studies on the pathogenesis of hyperuricemia should therefore focus on further elucidation of molecular mechanisms of renal uric transport and analyze pathogenetic links between metabolic disorders and hyperuricemia, including hormonal regulation and electrolyte disturbances, in more detail.

References

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