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

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.

Identification of a dysfunctional exon-skipping splice variant in GLUT9/SLC2A9 causal for renal hypouricemia type 2

“…A plausible explanation for this point would be that URAT1 but not GLUT9 might have backup machinery. Indeed, recent studies revealed that like URAT1, organic anion transporter 10 (also known as SLC22A13) has a physiological role as a renal urate re-absorber expressed on the apical side of renal proximal tubular cells though its contribution on renal urate handling is smaller than that of URAT1 ( Higashino et al, 2020 ; Toyoda et al, 2022 ). By contrast, on the basal side of the cells, no physiologically-important urate transporters have been identified to date, except for GLUT9.…”

Vitamin C transporter SVCT1 serves a physiological role as a urate importer: functional analyses and in vivo investigations

“…The Michaelis-Menten constant (K m ) and maximal velocity (V max ) of the SVCT1-or Svct1-mediated urate transport were determined by fitting the Michaelis-Menten model to experimental urate transport rates and concentrations using nonlinear regression curve fitting in GraphPad Prism 8 (GraphPad Software, San Diego, CA, USA), as described previously [49].…”

“…The SVCT1-mediated transport activities were expressed as a percentage of the control (100%). Using the least-squares method with Excel 2019 (Microsoft, Redmond, WA, USA), fitting curves were obtained based on the calculated values according to the following formula as described previously [49]:…”

“…Some SU-affecting drugs have been previously reported to inhibit physiologically important urate transporters with clinical implications via off-target interactions, including febuxostat-ABCG2 and losartan-organic anion transporter 10 (OAT10) [34,49]. However, there was no information on their effects on SVCT1.…”

Susceptibility genes of hyperuricemia and gout

“…Recent studies have also shown that dysfunctional missense mutation of SLC22A13 gene reduced SUA levels and the risk of gout. Meta-analysis displayed that rs117371763 (R377C) variant of SLC22A13 gene has significant anti-gout effect [ 56 ]. It is certain that SLC22A13 , like SLC22A12 , can provide effective targets for the treatment of gout.…”