2. Academic Validation
  3. OAT10/SLC22A13 Acts as a Renal Urate Re-Absorber: Clinico-Genetic and Functional Analyses With Pharmacological Impacts

OAT10/SLC22A13 Acts as a Renal Urate Re-Absorber: Clinico-Genetic and Functional Analyses With Pharmacological Impacts

  • Front Pharmacol. 2022 Apr 6;13:842717. doi: 10.3389/fphar.2022.842717.
Yu Toyoda 1 2,  Yusuke Kawamura 2,  Akiyoshi Nakayama 2,  Keito Morimoto 1,  Seiko Shimizu 2,  Yuki Tanahashi 2,  Takashi Tamura 3,  Takaaki Kondo 4,  Yasufumi Kato 3,  Kimiyoshi Ichida 5,  Hiroshi Suzuki 1,  Nariyoshi Shinomiya 2,  Yasushi Kobayashi 6,  Tappei Takada 1,  Hirotaka Matsuo 2
Affiliations

Affiliations

  • 1 Department of Pharmacy, The University of Tokyo Hospital, Tokyo, Japan.
  • 2 Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Saitama, Japan.
  • 3 Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Aichi, Japan.
  • 4 Program in Radiological and Medical Laboratory Sciences, Pathophysiological Laboratory Science, Nagoya University Graduate School of Medicine, Aichi, Japan.
  • 5 Department of Pathophysiology, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
  • 6 Department of Anatomy and Neurobiology, National Defense Medical College, Saitama, Japan.
PMID: 35462902 DOI: 10.3389/fphar.2022.842717
Abstract

Dysfunctional missense variant of organic anion transporter 10 (OAT10/SLC22A13), rs117371763 (c.1129C>T; p.R377C), is associated with a lower susceptibility to gout. OAT10 is a urate transporter; however, its physiological role in urate handling remains unclear. We hypothesized that OAT10 could be a renal urate re-absorber that will be a new molecular target of urate-lowering therapy like urate transporter 1 (URAT1, a physiologically-important well-known renal urate re-absorber) and aimed to examine the effect of OAT10 dysfunction on renal urate handling. For this purpose, we conducted quantitative trait locus analyses of serum urate and fractional excretion of uric acid (FEUA) using samples obtained from 4,521 Japanese males. Moreover, we performed immunohistochemical and functional analyses to assess the molecular properties of OAT10 as a renal urate transporter and evaluated its potential interaction with urate-lowering drugs. Clinico-genetic analyses revealed that carriers with the dysfunctional OAT10 variant exhibited significantly lower serum urate levels and higher FEUA values than the non-carriers, indicating that dysfunction of OAT10 increases renal urate excretion. Given the results of functional assays and immunohistochemical analysis demonstrating the expression of human OAT10 in the apical side of renal proximal tubular cells, our data indicate that OAT10 is involved in the renal urate reabsorption in renal proximal tubules from urine. Additionally, we found that renal OAT10 inhibition might be involved in the urate-lowering effect of losartan and lesinurad which exhibit uricosuric effects; indeed, losartan, an approved drug, inhibits OAT10 more strongly than URAT1. Accordingly, OAT10 can be a novel potential molecular target for urate-lowering therapy.

Keywords

lesinurad; losartan; renal urate handling; urate reabsorption inhibitor; urate transporter; urate-lowering therapy; uricosuric agent.

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