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Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board: Buchner, Johannes / Lei, Ming / Ludwig, Stephan / Thomas, Douglas D. / Turk, Boris / Wittinghofer, Alfred


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Volume 400, Issue 10

Issues

Organic anion transporters 1 and 3 influence cellular energy metabolism in renal proximal tubule cells

Jelle Vriend
  • Corresponding author
  • Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, P.O. Box 9101, NL-6500HB, Nijmegen, The Netherlands
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/ Charlotte A. Hoogstraten
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/ Tom J.J. Schirris
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/ Frans G.M. Russel
  • Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, P.O. Box 9101, NL-6500HB, Nijmegen, The Netherlands
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/ Rosalinde Masereeuw
  • Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Universiteitsweg 99, NL-3584CG, Utrecht, The Netherlands
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/ Martijn J. Wilmer
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Published Online: 2019-01-29 | DOI: https://doi.org/10.1515/hsz-2018-0446

Abstract

Organic anion transporters (OATs) 1 and 3 are, besides being uptake transporters, key in several cellular metabolic pathways. The underlying mechanisms are largely unknown. Hence, we used human conditionally immortalized proximal tubule epithelial cells (ciPTEC) overexpressing OAT1 or OAT3 to gain insight into these mechanisms. In ciPTEC-OAT1 and -OAT3, extracellular lactate levels were decreased (by 77% and 71%, respectively), while intracellular ATP levels remained unchanged, suggesting a shift towards an oxidative phenotype upon OAT1 or OAT3 overexpression. This was confirmed by increased respiration of ciPTEC-OAT1 and -OAT3 (1.4-fold), a decreased sensitivity to respiratory inhibition, and characterized by a higher demand on mitochondrial oxidative capacity. In-depth profiling of tricarboxylic acid (TCA) cycle metabolites revealed reduced levels of intermediates converging into α-ketoglutarate in ciPTEC-OAT1 and -OAT3, which via 2-hydroxyglutarate metabolism explains the increased respiration. These interactions with TCA cycle metabolites were in agreement with metabolomic network modeling studies published earlier. Further studies using OAT or oxidative phosphorylation (OXPHOS) inhibitors confirmed our idea that OATs are responsible for increased use and synthesis of α-ketoglutarate. In conclusion, our results indicate an increased α-ketoglutarate efflux by OAT1 and OAT3, resulting in a metabolic shift towards an oxidative phenotype.

This article offers supplementary material which is provided at the end of the article.

Keywords: α-ketoglutarate; cellular energy metabolism; OAT1; OAT3; renal proximal tubule epithelial cells; TCA cycle

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About the article

Received: 2018-11-30

Accepted: 2018-12-29

Published Online: 2019-01-29

Published in Print: 2019-09-25


Funding Source: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Award identifier / Grant number: 37497–25920

This project was supported by the NephroTube project funded by the National Center for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs), Funder Id: 10.13039/501100000849, under the Crack-it challenge 15 (Nephrotube) project no. 37497–25920. The authors thank Werner J. Koopman and Peter H. Willems (Department of Biochemistry, Radboud University Medical Center, Nijmegen, The Netherlands) for their input and advice regarding this study. The authors would also like to thank the microscopic imaging center at Radboud University Medical Center for using the imaging facilities.


Conflict of interest statement: M.J. Wilmer and F.G.M. Russel are co-inventors on patent EP2010/066792 ‘Novel conditionally immortalized human proximal tubule cell line expressing functional influx and efflux transporters’ assigned to Radboud University Medical Center and as such M.J. Wilmer and F.G.M. Russel have a conflict of interest through the commercialization of ciPTEC models via Cell4Pharma.


Citation Information: Biological Chemistry, Volume 400, Issue 10, Pages 1347–1358, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: https://doi.org/10.1515/hsz-2018-0446.

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