Uric acid transport and disease

Abstract

Uric acid is the metabolic end product of purine metabolism in humans. It has antioxidant properties that may be protective but can also be pro-oxidant, depending on its chemical microenvironment. Hyperuricemia predisposes to disease through the formation of urate crystals that cause gout, but hyperuricemia, independent of crystal formation, has also been linked with hypertension, atherosclerosis, insulin resistance, and diabetes. We discuss here the biology of urate metabolism and its role in disease. We also cover the genetics of urate transport, including URAT1, and recent studies identifying SLC2A9, which encodes the glucose transporter family isoform Glut9, as a major determinant of plasma uric acid levels and of gout development.

Figure 1. Pathways of urate homeostasis.

Summary scheme of the pathways to produce uric acid, to convert it into allantoin by the liver enzyme uricase, and to excrete it. The balance between these pathways regulates blood urate concentrations, which are higher in humans and apes due to inactivation of the uricase genes. Hyperuricemia can lead to gout and possibly to cardiovascular effects, whereas hyperuricosuria may leads to uric acid crystal–induced pathologies.

Figure 2. Antioxidant and pro-oxidant effect of uric acid.

Antioxidant activities. (A) Peroxynitrites (ONOO^–) are produced from the reaction of nitric oxide (NO•) with superoxide (O2^–•). Peroxynitrites can induce protein nitrosation and lipid and protein peroxidation and block tetrahydrobiopterin (HB4), a cofactor necessary for NOS activity. In the absence of HB4, NOS produces ROS. Uric acid (UA) can directly inactivate peroxynitrite by a reaction that generates uric acid radicals (UA•); these can be rapidly eliminated by plasma ascorbic acid. (B) Uric acid can also prevent Cu²⁺-induced oxidation of LDL, a reaction that may protect against atherosclerosis development. (C) By enhancing arginase activity, uric acid diverts l-arginine from NO production to urea production. Uric acid can also directly react with NO to generate nitrosated uric acid, and the nitroso group can then be transferred to glutathione (GSH) for transport to another recipient molecule. In the presence of oxygen, uric acid reacts with NO to produce the stable species 6-aminouracil. Uric acid uptake in adipocytes activates NADPH oxidase and increase production of ROS, which can initiate an inflammatory reaction. In vascular smooth muscle cells, uric acid can activate the NF-κB and MAPK pathway and increase cyclooxygenase and MCP-1 production. Blue arrows, chemical reactions; green arrows, products from enzymatic or signaling pathways; red arrows, activation of enzymatic activities.

Figure 3. Urate transporters in kidney epithelial cells of humans and mice.

In humans (upper left panel), the urate reabsorption pathway involves the apical exchanger proteins URAT1, OAT4, and OAT10; intracellular urate is released through basolateral Glut9. Urate uptake by URAT1 and OAT10 is accelerated by intracellular monocarboxylates such as lactate, pyrazinoate, and nicotinate and by dicarboxylates for OAT4. Several apical monocarboxylate transporters are required to favor urate reabsorption, such as MCT9 and SMCT1 and -2 (see text). The excretion pathway (blue box) involves the basolateral urate/dicarboxylate exchangers OAT1 and OAT3 and the apical ATP-binding cassette proteins MRP4 and ABCG2, as well as the sodium/phosphate cotransporters NPT1 and NPT4. Functional organization of the apical transporters is regulated by interactions with PDZ domains present in URAT1, NPT1, OAT4, and the sodium/monocarboxylate cotransporter SMCT1 and with PDZK1 and NHERF1; and influenced by changes in actin polymerization regulated by the protein CARMIL, as determined by biochemical and genetic studies (see text). Urate transport in the mouse kidney involves both the proximal and distal convoluted tubules (middle and lower left panels). The same urate-transporting proteins present in humans are found in the mouse proximal tubules, except for Glut9, which is present at an extremely low levels. In mice, in contrast to humans, Glut9 is present at very high levels in both the apical and basolateral poles of distal convoluted tubule cells. However, it is not known which isoform of Glut9 is present in the apical and basolateral membranes.

Figure 4. Summary of Glut9 sites of expression and function.

Glut9 plays an important role in the control of urate homeostasis by its role in several organs. In kidney, evidence strongly supports a major role of Glut9 in uric acid reabsorption; in intestine, Glut9 may participate in uric acid excretion, although there has been no direct testing of this hypothesis; in the liver of animals with active uricase, Glut9 is required for hepatic uric acid uptake and conversion to allantoin for excretion. Absence of uricase in humans raises the question of the role of hepatic Glut9 in humans. There is good evidence for Glut9 expression in chondrocytes and leukocytes, but so far there is no indication whether this transporter is required for uptake or secretion.