title: Glut9 is a major regulator of urate homeostasis and its genetic inactivation induces hyperuricosuria and urate nephropathy.
abstract: Elevated plasma urate levels are associated with metabolic, cardiovascular, and renal diseases. Urate may also form crystals, which can be deposited in joints causing gout and in kidney tubules inducing nephrolithiasis. In mice, plasma urate levels are controlled by hepatic breakdown, as well as, by incompletely understood renal processes of reabsorption and secretion. Here, we investigated the role of the recently identified urate transporter, Glut9, in the physiological control of urate homeostasis using mice with systemic or liver-specific inactivation of the Glut9 gene. We show that Glut9 is expressed in the basolateral membrane of hepatocytes and in both apical and basolateral membranes of the distal nephron. Mice with systemic knockout of Glut9 display moderate hyperuricemia, massive hyperuricosuria, and an early-onset nephropathy, characterized by obstructive lithiasis, tubulointerstitial inflammation, and progressive inflammatory fibrosis of the cortex, as well as, mild renal insufficiency. In contrast, liver-specific inactivation of the Glut9 gene in adult mice leads to severe hyperuricemia and hyperuricosuria, in the absence of urate nephropathy or any structural abnormality of the kidney. Together, our data show that Glut9 plays a major role in urate homeostasis by its dual role in urate handling in the kidney and uptake in the liver.
authors.affiliation: Mouse Metabolic Facility of the Cardiomet Center, University Hospital, 1011 Lausanne, Switzerland.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Preitner
authors.forename: Olivier
authors.initials: O
authors.lastname: Bonny
authors.forename: Alexandra
authors.initials: A
authors.lastname: Laverrière
authors.forename: Samuel
authors.initials: S
authors.lastname: Rotman
authors.forename: Dmitri
authors.initials: D
authors.lastname: Firsov
authors.forename: Anabela
authors.initials: A
authors.lastname: Da Costa
authors.forename: Salima
authors.initials: S
authors.lastname: Metref
authors.forename: Bernard
authors.initials: B
authors.lastname: Thorens
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D051246:Glucose Transport Proteins, Facilitative / Q000235:genetics* / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009395:Nephritis, Interstitial / Q000235:genetics*; D009399:Nephrons / Q000378:metabolism; D014527:Uric Acid / Q000378:metabolism* / Q000652:urine*
chemical_list: D051246:Glucose Transport Proteins, Facilitative; C498775:Slc2a9 protein, mouse; D014527:Uric Acid
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