Role of Organic Anion Transporter NPT4 in Renal Handling of Uremic Toxin 3-indoxyl Sulfate.

Autor: Imamura R; Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan., Sugimoto M; Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0052, Japan., Horike SI; Research Center for Experimental Modeling of Human Disease, Kanazawa University, Kanazawa 920-0934, Japan., Terakawa J; Laboratory of Toxicology, School of Veterinary Medicine, Azabu University, Sagamihara, Kanagawa 252-5201, Japan., Fujita K; Faculty of Pharmaceutical Science, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan., Tamai I; Faculty of Pharmaceutical Science, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan., Daikoku T; Research Center for Experimental Modeling of Human Disease, Kanazawa University, Kanazawa 920-0934, Japan., Kato Y; Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan., Arakawa H; Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan. Electronic address: arakawa@p.kanazawa-u.ac.jp.
Jazyk: angličtina
Zdroj: Journal of pharmaceutical sciences [J Pharm Sci] 2024 Jul; Vol. 113 (7), pp. 1996-2000. Date of Electronic Publication: 2024 Apr 18.
DOI: 10.1016/j.xphs.2024.04.014
Abstrakt: Sodium-phosphate transporter NPT4 (SLC17A3) is a membrane transporter for organic anionic compounds localized on the apical membranes of kidney proximal tubular epithelial cells and plays a role in the urinary excretion of organic anionic compounds. However, its physiological role has not been sufficiently elucidated because its substrate specificity is yet to be determined. The present study aimed to comprehensively explore the physiological substrates of NPT4 in newly developed Slc17a3 -/- mice using a metabolomic approach. Metabolomic analysis showed that the plasma concentrations of 11 biological substances, including 3-indoxyl sulfate, were more than two-fold higher in Slc17a3 -/- mice than in wild-type mice. Moreover, urinary excretion of 3-indoxyl sulfate was reduced in Slc17a3 -/- mice compared to that in wild-type mice. The uptake of 3-indoxyl sulfate by NPT4-expressing Xenopus oocytes was significantly higher than that by water-injected oocytes. The calculated K m and V max values for NPT4-mediated 3-indoxyl sulfate uptake were 4.52 ± 1.18 mM and 1.45 ± 0.14 nmol/oocyte/90 min, respectively. In conclusion, the present study revealed that 3-indoxyl sulfate is a novel substrate of NPT4 based on the metabolomic analysis of Slc17a3 -/- mice, suggesting that NPT4 regulates systemic exposure to 3-indoxyl sulfate by regulating its urinary excretion.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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