Glut9 is a major regulator of urate homeostasis and its genetic inactivation induces hyperuricosuria and urate nephropathy.
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.
Preitner
Frédéric
F
Mouse Metabolic Facility of the Cardiomet Center, University Hospital, 1011 Lausanne, Switzerland.
Bonny
Olivier
O
Laverrière
Alexandra
A
Rotman
Samuel
S
Firsov
Dmitri
D
Da Costa
Anabela
A
Metref
Salima
S
Thorens
Bernard
B
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*
D051246:Glucose Transport Proteins, Facilitative; C498775:Slc2a9 protein, mouse; D014527:Uric Acid
Semin Nephrol. 2005 Jan;25(1):43-9
15660334
Nature. 2006 Mar 9;440(7081):237-41
16407889
N Engl J Med. 2008 Oct 23;359(17):1811-21
18946066
Nat Genet. 2008 Apr;40(4):437-42
18327257
Nature. 2002 May 23;417(6887):447-52
12024214
Physiol Genomics. 2008 Apr 22;33(2):180-92
18270321
Proc Natl Acad Sci U S A. 1994 Jan 18;91(2):742-6
8290593
J Appl Physiol Respir Environ Exerc Physiol. 1977 Dec;43(6):1102-5
606696
Nutr Metab (Lond). 2004 Oct 19;1(1):10
15507132
J Biol Chem. 2004 Apr 16;279(16):16229-36
14739288
Curr Opin Immunol. 2007 Dec;19(6):615-22
17977705
Nat Clin Pract Oncol. 2006 Aug;3(8):438-47
16894389
Am J Hum Genet. 2008 Dec;83(6):744-51
19026395
PLoS Med. 2008 Oct 7;5(10):e197
18842065
Physiology (Bethesda). 2005 Apr;20:125-33
15772301
Am J Physiol Renal Physiol. 2006 Feb;290(2):F251-61
16403838
Cell Physiol Biochem. 2003;13(5):249-56
14586168
J Am Soc Nephrol. 2004 Feb;15(2):261-8
14747372
Mol Endocrinol. 2006 Mar;20(3):686-97
16293642
Science. 1980 Oct 3;210(4465):15-22
6997992
PLoS Genet. 2007 Nov;3(11):e194
17997608
Nat Genet. 2008 Apr;40(4):430-6
18327256
J Am Soc Nephrol. 2007 Feb;18(2):430-9
17229912
J Biol Chem. 1997 Jul 25;272(30):18526-9
9228014
Lancet. 2008 Dec 6;372(9654):1953-61
18834626
J Biol Chem. 2008 Oct 3;283(40):26834-8
18701466
J Hypertens. 2008 Nov;26(11):2085-92
18854744
J Am Soc Nephrol. 2001 May;12(5):1001-1009
11316859