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THU0459 Exploring dual modulation of GLUT9 and OAT3, an apical and basolateral transporters in proximal tubules and experimental mice
  1. SH Lee,
  2. SB Kim,
  3. D-S Oh
  1. The K-herb Research Centre, Korea Institute of Oriental Medicine, Daejeon, Korea, Republic Of

Abstract

Background Uric acid homeostasis is a set of the balance in glomerular filtration, tubular secretion, reabsorption, and excretion. In the course of cascade, two kinds play a pivotal role; efflux transporters in apical at renal proximal tubular membrane, uptake ones in basolateral at membrane. The former has been of interest in the targets for uricosuric effects, however, dual modulation of the two could keep uric acid balance in stable ways.

Objectives The aim of this study was to assess the uptake of seven test articles in the course of the expressions of apical/basolateral transporters in potassium oxonate (PO)-treated kidney epithelial cell lines (Caco-2, MDCK, LLC-PK1) and ICR mice.

Methods The selected cell lines were treated with potassium oxonate (0.25 mM) and then modulated by seven test articles, the commercial herbal products (SITK01 through SITK06 and SITT01) at dose range of 0.015–1 mg/mL. To determine efficacious dose range by each test article, three cell lines, Caco-2, MDCK and LLC-PK1 cells were assessed with MTT assay. Forty eight ICR mice were injected intraperitoneally with PO at a dose of 200 and 400 mg/kg and then blood draws were conducted 0, 6, 12, 24, 72 hours after PO administration. The levels of uric acid and transporters were also measured by ELISA assay and Western blotting analysis in those cell lines.

Results Treatment of SITK01 through SITK03 and SITT01 at concentration (250 mg/mL) decreased the cell viability. The PO-stimulated kidney epithelial cells with SITK01 through SITK03 treatment increased GLUT9 by 2.5 folds and decreased OAT3 by 1.5 folds (versus controls, p=0.012, and p=0.017, respectively). In PO-treated mice, uric acid levels were increased through GLUT9 and OAT3 transporters. The results indicated that SITK01, SITK02, and SITK03 showed the potential on uricosuric effects in a dual modulation of apical/basolateral sides of kidney epithelial tubular membranes.

Table 1.

Protein expression of transporters in apical and basolateral membranes of proximal tubular epithelial cells and potassium oxonate-treated experimental mice

Conclusions The present findings demonstrated that three commercial herbal products showed potentials to reduce hyperuricaemia-induced condition by changing protein expression levels in a transporter-uptake assay. The OAT3 and GLUT9 could be further investigated as the uricosuric group-targets on the bilateral sides at kidney epithelial tubular membranes.

References

  1. Fromm MF, König J. Transporters and drug-drug interactions: important determinants of drug disposition and effects. 2015 Nature Reviews Drug Discovery 14, 543–560.

  2. Giacomini KM, Lawrence Lin, Sook Wah Yee, Richard B. Kim & Kathleen. SLC transporters as therapeutic targets: emerging opportunities. 2015 Nature Reviews Drug Discovery 14, 543–560.

References

Acknowledgements This study was supported by the Traditional Korean Medicine R&D program funded by the Ministry of Health & Welfare through the Korea Health Industry Development Institute (KHIDI, Grant # HI16C0864). The commercial products were donated by the virtue of Kracie Pharma, Ltd. and Tsumura & Co.

Disclosure of Interest None declared

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