Urate Transporters in the Kidney: What Clinicians Need to Know

Abstract

Urate is produced in the liver by the degradation of purines from the diet and nucleotide turnover and excreted by the kidney and gut. The kidney is the major route of urate removal and has a pivotal role in the regulation of urate homeostasis. Approximately 10% of the glomerular filtered urate is excreted in the urine, and the remainder is reabsorbed by the proximal tubule. However, the transport of urate in the proximal tubule is bidirectional: reabsorption and secretion. Thus, an increase in reabsorption or a decrease in secretion may induce hyperuricemia. In contrast, a decrease in reabsorption or an increase in secretion may result in hyperuricosuria. In the proximal tubule, urate reabsorption is mainly mediated by apical URAT1 ( SLC22A12 ) and basolateral GLUT9 ( SLC2A9 ) transporter. OAT4 ( SLC22A11 ) also acts in urate reabsorption in the apical membrane, and its polymorphism is associated with the risk of hyperuricemia. Renal hypouricemia is caused by SLC22A12 or SLC2A9 loss-of-function mutations, and it may be complicated by exercise-induced acute kidney injury. URAT1 and GLUT9 are also drug targets for uricosuric agents. Sodium-glucose cotransporter inhibitors may induce hyperuricosuria by inhibiting GLUT9b located in the apical plasma membrane. Urate secretion is mediated by basolateral OAT1 ( SLC22A6 ) and OAT3 ( SLC22A8 ) and apical ATP-binding cassette super-family G member 2 ( ABCG2 ), NPT1 ( SLC17A1 ), and NPT4 ( SLC17A3 ) transporter in the proximal tubule. NPT1 and NPT4 may be key players in renal urate secretion in humans, and deletion of SLC22A6 and SLC22A8 in mice leads to decreased urate excretion. Dysfunctional variants of ABCG2 inhibit urate secretion from the gut and kidney and may cause gout. In summary, the net result of urate transport in the proximal tubule is determined by the dominance of transporters between reabsorption (URAT1, OAT4, and GLUT9) and secretion (ABCG2, NPT1, NPT4, OAT1, and OAT3).

Gender-specific dimorphic association between bicarbonate and uric acid serum levels among healthy adults. Qatar Biobank data

“…Thus, it is important to understand the gender variation and the physiological mechanisms controlling uric acid to explain the ndings in this study. As mentioned earlier, the renal handling of uric acid is the main regulatory mechanism that determines its level by the reabsorption and excretion processes by different transporter proteins in the proximal convoluted tubule of the nephron (19)(20)(21). The homeostatic regulation of uric acid by the kidney includes the initial reabsorption of 95% of the initial ltered uric acid by OAT family transporters (organic anion transporter 3,4,10 and GLUT9 (22).…”

Trends in the Contribution of Genetic Susceptibility Loci to Hyperuricemia and Gout and Associated Novel Mechanisms

“…A high serum uric acid concentration is the primary risk factor for gout. Controlling the metabolism of uric acid in circulation at reasonable levels plays a vital role in preventing and improving gout ( Chung and Kim, 2021 ). The progression from high blood uric acid levels to gout occurs in three main steps, hyperuricemia, the deposition of monosodium urate crystals, and inflammatory responses in the joints ( Dalbeth et al, 2016 ).…”

Susceptibility genes of hyperuricemia and gout

“…2 ). SLC22A12 gene dysfunctional mutations cause URAT1 dysfunction, then leading to hereditary renal hypouricemia type 1 (RHUC1), which is characterized by decreased SUA levels and increased UA excretion [ 45 ]. Epidemiological investigation showed that 90% of hypouricemia (SUA ≤ 2.0 mg/dl) was caused by nonfunctional URAT1 mutations [ 46 ].…”

“…Among them, rs16890979 was associated with lower gout risk in Caucasians and Asians, rs1014290 was associated with lower gout risk in Asians, and rs12510549 was associated with lower gout risk in Caucasians [ 62 ]. SLC2A9 rs3733591 (Arg265His) variant increases the risk of gout [ 45 ]. SLC2A9 rs 737267, rs6449213 and rs1014290 are associated with gout in the UK, German and Croatian populations, respectively [ 45 ].…”

“…SLC2A9 rs3733591 (Arg265His) variant increases the risk of gout [ 45 ]. SLC2A9 rs 737267, rs6449213 and rs1014290 are associated with gout in the UK, German and Croatian populations, respectively [ 45 ]. SLC2A9 rs3775948G and rs13129697G alleles reduce the risk of HUA [ 63 ].…”