Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.


Tranilast Inhibits Urate Transport Mediated by URAT1 and GLUT9.

Mandal3,  Asim, Emerling1,  Daniel, Serafini1,  Tito, Mount2,  David B.

Nuon Therapeutics, Inc., San Mateo, CA 94403
Renal Division, VA Boston Healthcare System and Brigham & Women's Hospital, Harvard Medical School, Boston, MA
Renal Division, VA Boston Healthcare System and Brigham & Women's Hospital, Harvard Medical School, Boston, MA 02115

Background:

Gout is a disease first described nearly five millennia ago that still has a large unmet need and a growing incidence. Gout occurs when crystals of monosodium urate (MSU), deposited in joints and soft tissues, lead to acute as well as chronic, local and systemic inflammation. Treatment of gout has focused on chronic treatment of the underlying hyperuricemia that leads to MSU crystal deposition. The kidney mediates two thirds of urate elimination, excreting urate as the net sum of absorption and secretion in the proximal tubule. In humans, proximal tubular urate reabsorption of urate from the glomerular filtrate requires the apical urate-anion exchanger URAT1; basolateral exit is accomplished by GLUT9. Loss of function in either protein is a genetic cause of renal hypouricemia; more common variants in GLUT9 exert a significant effect on serum uric acid. Tranilast, the active ingredient of a drug marketed in Japan and South Korea, has recently been shown both to lower serum uric acid in humans via a uricosuric mechanism and to suppress MSU crystal-mediated inflammatory responses in a animal model of gouty inflammation. Given the critical roles of GLUT9 and URAT1 in urate homeostasis, we determined the effect of tranilast on these two transporters.

Objectives:

To determine if tranilast can inhibit urate transport mediated by the two key reabsorptive urate transporters, URAT1 (SLC22A12) and GLUT9 (SLC2A9).

Methods:

Urate transport assays were established in Xenopus oocytes, injecting cRNA transcribed in vitro from expression constructs in the pGEMHE vector. Constructs were generated from full-length cDNAs encoding the long form of human GLUT9 (Genbank sequence BC110414) and human URAT1 (BC053348). [14C]Uric acid was used to monitor transport. Tranilast was prepared in a DMSO stock solution and diluted immediately prior to use. Benzbromarone was utilized as a positive inhibition control for both GLUT9 and URAT1.

Results:

Urate transport was robust in Xenopus oocytes injected with GLUT9 and URAT1 cRNAs, with urate uptakes as much as 45-fold and 26-fold higher, respectively, than in buffer-injected controls. Urate transport via GLUT9 in this system was inhibited by tranilast with an IC50 of approximately 16 microM. Likewise, tranilast inhibited urate transport mediated by URAT1, with an IC50 of approximately 24 microM.

Conclusions:

Tranilast can inhibit urate transport through both GLUT9 and URAT1 proteins, with an IC50 consistent in each case with the level of exposure in humans resulting from doses that produce a uricosuric effect. This suggests that the uricosuric activity of tranilast is due to inhibition of these reabsorptive urate transporters in the kidney.

To cite this abstract, please use the following information:
Mandal, Asim, Emerling, Daniel, Serafini, Tito, Mount, David B.; Tranilast Inhibits Urate Transport Mediated by URAT1 and GLUT9. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :164
DOI: 10.1002/art.27933

Abstract Supplement

Meeting Menu

2010 ACR/ARHP