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

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Veröffentlicht/Copyright: 17. Januar 2019
Biological Chemistry
Aus der Zeitschrift Biological Chemistry Band 400 Heft 10

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.

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

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

Award Identifier / Grant number: 37497–25920

Funding statement: 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.

  1. 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.

References

Ahn, S.Y., Jamshidi, N., Mo, M.L., Wu, W., Eraly, S.A., Dnyanmote, A., Bush, K.T., Gallegos, T.F., Sweet, D.H., Palsson, B.O., et al. (2011). Linkage of organic anion transporter-1 to metabolic pathways through integrated “omics”-driven network and functional analysis. J. Biol. Chem. 286, 31522–31531.10.1074/jbc.M111.272534Suche in Google Scholar PubMed PubMed Central

Brandt, U., Schagger, H., and von Jagow, G. (1988). Characterisation of binding of the methoxyacrylate inhibitors to mitochondrial cytochrome c reductase. Eur. J. Biochem. 173, 499–506.10.1111/j.1432-1033.1988.tb14026.xSuche in Google Scholar PubMed

Bush, K.T., Wu, W., Lun, C., and Nigam, S.K. (2017). The drug transporter oat3 (slc22a8) and endogenous metabolite communication via the gut-liver-kidney axis. J. Biol. Chem. 292, 15789–15803.10.1074/jbc.M117.796516Suche in Google Scholar PubMed PubMed Central

Engqvist, M.K., Esser, C., Maier, A., Lercher, M.J., and Maurino, V.G. (2014). Mitochondrial 2-hydroxyglutarate metabolism. Mitochondrion 19, 275–281.10.1016/j.mito.2014.02.009Suche in Google Scholar PubMed

Eraly, S.A., Blantz, R.C., Bhatnagar, V., and Nigam, S.K. (2003). Novel aspects of renal organic anion transporters. Curr. Opin. Nephrol. Hypertens. 12, 551–558.10.1097/00041552-200309000-00011Suche in Google Scholar PubMed

Eraly, S.A., Vallon, V., Vaughn, D.A., Gangoiti, J.A., Richter, K., Nagle, M., Monte, J.C., Rieg, T., Truong, D.M., Long, J.M., et al. (2006). Decreased renal organic anion secretion and plasma accumulation of endogenous organic anions in oat1 knock-out mice. J. Biol. Chem. 281, 5072–5083.10.1074/jbc.M508050200Suche in Google Scholar PubMed

Fedecostante, M., Westphal, K.G.C., Buono, M.F., Sanchez Romero, N., Wilmer, M.J., Kerkering, J., Baptista, P.M., Hoenderop, J.G., and Masereeuw, R. (2018). Recellularized native kidney scaffolds as a novel tool in nephrotoxicity screening. Drug Metab. Dispos. 46, 1338–1350.10.1124/dmd.118.080721Suche in Google Scholar PubMed

Janssen, A.J., Trijbels, F.J., Sengers, R.C., Wintjes, L.T., Ruitenbeek, W., Smeitink, J.A., Morava, E., van Engelen, B.G., van den Heuvel, L.P., and Rodenburg, R.J. (2006). Measurement of the energy-generating capacity of human muscle mitochondria: diagnostic procedure and application to human pathology. Clin. Chem. 52, 860–871.10.1373/clinchem.2005.062414Suche in Google Scholar PubMed

Kaufhold, M., Schulz, K., Breljak, D., Gupta, S., Henjakovic, M., Krick, W., Hagos, Y., Sabolic, I., Burckhardt, B.C., and Burckhardt, G. (2011). Differential interaction of dicarboxylates with human sodium-dicarboxylate cotransporter 3 and organic anion transporters 1 and 3. Am. J. Physiol. Renal Physiol. 301, F1026–1034.10.1152/ajprenal.00169.2011Suche in Google Scholar PubMed

Koopman, W.J., Verkaart, S., Visch, H.J., van der Westhuizen, F.H., Murphy, M.P., van den Heuvel, L.W., Smeitink, J.A., and Willems, P.H. (2005). Inhibition of complex I of the electron transport chain causes O2-.-mediated mitochondrial outgrowth. Am. J. Physiol. Cell Physiol. 288, C1440–1450.10.1152/ajpcell.00607.2004Suche in Google Scholar PubMed

Liemburg-Apers, D.C., Schirris, T.J., Russel, F.G., Willems, P.H., and Koopman, W.J. (2015). Mitoenergetic dysfunction triggers a rapid compensatory increase in steady-state glucose flux. Biophys. J. 109, 1372–1386.10.1016/j.bpj.2015.08.002Suche in Google Scholar PubMed PubMed Central

Liu, H.C., Jamshidi, N., Chen, Y., Eraly, S.A., Cho, S.Y., Bhatnagar, V., Wu, W., Bush, K.T., Abagyan, R., Palsson, B.O., et al. (2016). An organic anion transporter 1 (oat1)-centered metabolic network. J. Biol. Chem. 291, 19474–19486.10.1074/jbc.M116.745216Suche in Google Scholar PubMed PubMed Central

Masereeuw, R., van Pelt, A.P., van Os, S.H., Willems, P.H., Smits, P., and Russel, F.G. (2000). Probenecid interferes with renal oxidative metabolism: a potential pitfall in its use as an inhibitor of drug transport. Br. J. Pharmacol. 131, 57–62.10.1038/sj.bjp.0703541Suche in Google Scholar PubMed PubMed Central

Nagai, J., Yano, I., Hashimoto, Y., Takano, M., and Inui, K. (1998). Efflux of intracellular alpha-ketoglutarate via p-aminohippurate/dicarboxylate exchange in ok kidney epithelial cells. J. Pharmacol. Exp. Ther. 285, 422–427.Suche in Google Scholar

Nieskens, T.T., Peters, J.G., Schreurs, M.J., Smits, N., Woestenenk, R., Jansen, K., van der Made, T.K., Roring, M., Hilgendorf, C., Wilmer, M.J., et al. (2016). A human renal proximal tubule cell line with stable organic anion transporter 1 and 3 expression predictive for antiviral-induced toxicity. AAPS J. 18, 465–475.10.1208/s12248-016-9871-8Suche in Google Scholar PubMed PubMed Central

Nigam, S.K., Wu, W., Bush, K.T., Hoenig, M.P., Blantz, R.C., and Bhatnagar, V. (2015). Handling of drugs, metabolites, and uremic toxins by kidney proximal tubule drug transporters. Clin. J. Am. Soc. Nephrol. 10, 2039–2049.10.2215/CJN.02440314Suche in Google Scholar PubMed PubMed Central

O’Connor, P.M. (2006). Renal oxygen delivery: Matching delivery to metabolic demand. Clin. Exp. Pharmacol. Physiol. 33, 961–967.10.1111/j.1440-1681.2006.04475.xSuche in Google Scholar PubMed

Pagliarini, D.J., Calvo, S.E., Chang, B., Sheth, S.A., Vafai, S.B., Ong, S.E., Walford, G.A., Sugiana, C., Boneh, A., Chen, W.K., et al. (2008). A mitochondrial protein compendium elucidates complex I disease biology. Cell 134, 112–123.10.1016/j.cell.2008.06.016Suche in Google Scholar PubMed PubMed Central

Peters, E., Schirris, T., van Asbeck, A.H., Gerretsen, J., Eymael, J., Ashikov, A., Adjobo-Hermans, M.J., Russel, F., Pickkers, P., and Masereeuw, R. (2017). Effects of a human recombinant alkaline phosphatase during impaired mitochondrial function in human renal proximal tubule epithelial cells. Eur. J. Pharmacol. 796, 149–157.10.1016/j.ejphar.2016.12.034Suche in Google Scholar PubMed

Pritchard, J.B. (1988). Coupled transport of p-aminohippurate by rat kidney basolateral membrane vesicles. Am. J. Physiol. 255, F597–604.10.1152/ajprenal.1988.255.4.F597Suche in Google Scholar PubMed

Schindelin, J., Arganda-Carreras, I., Frise, E., Kaynig, V., Longair, M., Pietzsch, T., Preibisch, S., Rueden, C., Saalfeld, S., Schmid, B., et al. (2012). Fiji: an open-source platform for biological-image analysis. Nat. Methods 9, 676–682.10.1038/nmeth.2019Suche in Google Scholar PubMed PubMed Central

Shimada, H., Moewes, B., and Burckhardt, G. (1987). Indirect coupling to na+ of p-aminohippuric acid uptake into rat renal basolateral membrane vesicles. Am. J. Physiol. 253, F795–801.10.1152/ajprenal.1987.253.5.F795Suche in Google Scholar PubMed

Struys, E.A., Gibson, K.M., and Jakobs, C. (2007). Novel insights into l-2-hydroxyglutaric aciduria: Mass isotopomer studies reveal 2-oxoglutaric acid as the metabolic precursor of l-2-hydroxyglutaric acid. J. Inherit. Metab. Dis. 30, 690–693.10.1007/s10545-007-0697-5Suche in Google Scholar PubMed

Suter-Dick, L., Mauch, L., Ramp, D., Caj, M., Vormann, M.K., Hutter, S., Lanz, H.L., Vriend, J., Masereeuw, R., and Wilmer, M.J. (2018). Combining extracellular mirna determination with microfluidic 3d cell cultures for the assessment of nephrotoxicity: a proof of concept study. AAPS J. 20, 86.10.1208/s12248-018-0245-2Suche in Google Scholar PubMed

Vallon, V., Eraly, S.A., Wikoff, W.R., Rieg, T., Kaler, G., Truong, D.M., Ahn, S.Y., Mahapatra, N.R., Mahata, S.K., Gangoiti, J.A., et al. (2008). Organic anion transporter 3 contributes to the regulation of blood pressure. J. Am. Soc. Nephrol. 19, 1732–1740.10.1681/ASN.2008020180Suche in Google Scholar PubMed PubMed Central

Vriend, J., Nieskens, T.T.G., Vormann, M.K., van den Berge, B.T., van den Heuvel, A., Russel, F.G.M., Suter-Dick, L., Lanz, H.L., Vulto, P., Masereeuw, R., et al. (2018). Screening of drug-transporter interactions in a 3d microfluidic renal proximal tubule on a chip. AAPS J. 20, 87.10.1208/s12248-018-0247-0Suche in Google Scholar PubMed

Wikoff, W.R., Nagle, M.A., Kouznetsova, V.L., Tsigelny, I.F., and Nigam, S.K. (2011). Untargeted metabolomics identifies enterobiome metabolites and putative uremic toxins as substrates of organic anion transporter 1 (oat1). J. Proteome. Res. 10, 2842–2851.10.1021/pr200093wSuche in Google Scholar PubMed PubMed Central

Wilmer, M.J., Saleem, M.A., Masereeuw, R., Ni, L., van der Velden, T.J., Russel, F.G., Mathieson, P.W., Monnens, L.A., van den Heuvel, L.P., and Levtchenko, E.N. (2010). Novel conditionally immortalized human proximal tubule cell line expressing functional influx and efflux transporters. Cell Tissue Res. 339, 449–457.10.1007/s00441-009-0882-ySuche in Google Scholar PubMed PubMed Central

Wu, W., Jamshidi, N., Eraly, S.A., Liu, H.C., Bush, K.T., Palsson, B.O., and Nigam, S.K. (2013). Multispecific drug transporter slc22a8 (oat3) regulates multiple metabolic and signaling pathways. Drug Metab. Dispos. 41, 1825–1834.10.1124/dmd.113.052647Suche in Google Scholar PubMed PubMed Central

Wu, W., Bush, K.T., and Nigam, S.K. (2017). Key role for the organic anion transporters, oat1 and oat3, in the in vivo handling of uremic toxins and solutes. Sci. Rep. 7, 4939.10.1038/s41598-017-04949-2Suche in Google Scholar PubMed PubMed Central

Supplementary Material

The online version of this article offers supplementary material (https://doi.org/10.1515/hsz-2018-0446.

Received: 2018-11-30
Accepted: 2018-12-29
Published Online: 2019-01-17
Published in Print: 2019-10-25

© 2019 Walter de Gruyter GmbH, Berlin/Boston

Artikel in diesem Heft

  1. Frontmatter
  2. Spotlight on biomembranes – the 11th Transport Colloquium
  3. ABCB4/MDR3 in health and disease – at the crossroads of biochemistry and medicine
  4. Staphylococcus aureus α-toxin: small pore, large consequences
  5. 19F NMR as a versatile tool to study membrane protein structure and dynamics
  6. Mg2+ homeostasis and transport in cyanobacteria – at the crossroads of bacterial and chloroplast Mg2+ import
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  8. Exofacial phospholipids at the plasma membrane: ill-defined targets for early infection processes
  9. Aryl hydrocarbon receptor ligands increase ABC transporter activity and protein expression in killifish (Fundulus heteroclitus) renal proximal tubules
  10. Organic anion transporters 1 and 3 influence cellular energy metabolism in renal proximal tubule cells
  11. CFTR structure, stability, function and regulation
  12. Homo- and heterodimerization is a common feature of the solute carrier family SLC10 members
  13. Research Articles/Short Communications
  14. Cell Biology and Signaling
  15. Identification of the molecular determinants for nuclear import of PRV EP0
https://doi.org/10.1515/hsz-2018-0446
Schlagwörter für diesen Artikel
α-ketoglutarate; cellular energy metabolism; OAT1; OAT3; renal proximal tubule epithelial cells; TCA cycle

Artikel in diesem Heft

  1. Frontmatter
  2. Spotlight on biomembranes – the 11th Transport Colloquium
  3. ABCB4/MDR3 in health and disease – at the crossroads of biochemistry and medicine
  4. Staphylococcus aureus α-toxin: small pore, large consequences
  5. 19F NMR as a versatile tool to study membrane protein structure and dynamics
  6. Mg2+ homeostasis and transport in cyanobacteria – at the crossroads of bacterial and chloroplast Mg2+ import
  7. How RCK domains regulate gating of K+ channels
  8. Exofacial phospholipids at the plasma membrane: ill-defined targets for early infection processes
  9. Aryl hydrocarbon receptor ligands increase ABC transporter activity and protein expression in killifish (Fundulus heteroclitus) renal proximal tubules
  10. Organic anion transporters 1 and 3 influence cellular energy metabolism in renal proximal tubule cells
  11. CFTR structure, stability, function and regulation
  12. Homo- and heterodimerization is a common feature of the solute carrier family SLC10 members
  13. Research Articles/Short Communications
  14. Cell Biology and Signaling
  15. Identification of the molecular determinants for nuclear import of PRV EP0
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