SLC2A9 (GLUT9) mediates urate reabsorption in the mouse kidney

Abstract

Uric acid (UA) is a metabolite of purine degradation and is involved in gout flairs and kidney stones formation. GLUT9 (SLC2A9) was previously shown to be a urate transporter in vitro. In vivo, humans carrying GLUT9 loss-of-function mutations have familial renal hypouricemia type 2, a condition characterized by hypouricemia, UA renal wasting associated with kidney stones, and an increased propensity to acute renal failure during strenuous exercise. Mice carrying a deletion of GLUT9 in the whole body are hyperuricemic and display a severe nephropathy due to intratubular uric acid precipitation. However, the precise role of GLUT9 in the kidney remains poorly characterized. We developed a mouse model in which GLUT9 was deleted specifically along the whole nephron in a tetracycline-inducible manner (subsequently called kidney-inducible KO or kiKO). The urate/creatinine ratio was increased as early as 4 days after induction of the KO and no GLUT9 protein was visible on kidney extracts. kiKO mice are morphologically identical to their wild-type littermates and had no spontaneous kidney stones. Twenty-four-hour urine collection revealed a major increase of urate urinary excretion rate and of the fractional excretion of urate, with no difference in urate concentration in the plasma. Polyuria was observed, but kiKO mice were still able to concentrate urine after water restriction. KiKO mice displayed lower blood pressure accompanied by an increased heart rate. Overall, these results indicate that GLUT9 is a crucial player in renal handling of urate in vivo and a putative target for uricosuric drugs.Electronic supplementary materialThe online version of this article (10.1007/s00424-018-2190-4) contains supplementary material, which is available to authorized users.

The Time-Feature of Uric Acid Excretion in Hyperuricemia Mice Induced by Potassium Oxonate and Adenine

“…On the apical membrane of proximal tubular epithelial cells, ABCG2, NPT1, sodium-dependent phosphate transport protein 4 (NPT4) and multidrug-resistance-proteins MRP4 (ABCC4) have all been shown to contribute to the secretory transport of urate from proximal tubular epithelial cells into the tubule lumen [ 35 ]. The reabsorption transporter includes URAT1 localized on the apical membrane of renal proximal tubular epithelial cells, which transport uric acid from the tubule lumen to proximal tubule epithelial cells, the short isoform of GLUT9 on the apical membrane; its function is similar to URAT1 [ 16 , 25 ]. The long isoform of GLUT9 localized on the basolateral membranes of proximal tubular epithelial cells, which transport urate from renal tubular epithelial cells to the blood [ 2 ].…”

“…Kidney is the most important organ to excrete UA. Clinically, the most common causes of hyperuricemia are insufficient excretion of UA in the kidney, downregulation of UA secretion transporter (urate-anion transporter 1 (URAT1), glucose transporter 9 (GLUT9), et al) [ 15 , 16 ] and up-regulation of reabsorption transporter (ATP-binding cassette super family G number 2 (ABCG2), organic anion transporter 1 (OAT1), sodium-dependent phosphate cotransporter 1 (NPT1), et al) [ 17 , 18 , 19 ]. However, drugs with improving effects on UA excretion are rare.…”

A model of uric acid transport in the rat proximal tubule

“…Microdissection of rat tubules. Male Sprague-Dawley rats weighing 346 g on average were deeply anesthetized, and their kidneys were microdissected, as previously described (5,91). In brief, after deep anesthesia with Ketanarkon intraperitoneally (100 g/g body wt, Streuli, Pharma) and Rompun (10 g/g body wt, Bayer, Leverkusen, Germany), the left kidney was isolated and perfused with DMEM-F-12 (1:1, Life Technologies, Carlsbad, CA) supplemented with 40 mg/ml Liberase (Roche).…”

Personalized Medicine of Urate-Lowering Therapy for Gout

“…The encoded protein is involved in p21-activated protein kinase (PAK) pathway for transport of glucose, bile salts, organic acids, metal ions and amine compounds. Recent studies showed that GLUT-9 was participated in renal and gut excretion of uric acid and was implicated in antioxidant defense [41][42][43]. There are two distinct N-terminal isoforms of human GLUT-9: GLUT-9a (540 residues) and GLUT-9b (511 residues) [44].…”