Remote sensing and signaling in kidney proximal tubules stimulates gut microbiome-derived organic anion secretion
Jansen, Jitske; Jansen, Katja; Neven, Ellen; Poesen, Ruben; Othman, Amr; van Mil, Alain; Sluijter, Joost; Torano, Javier Sastre; Zaal, Esther A.; Berkers, Celia R.; Esser, Diederik; Wichers, Harry J.; van Ede, Karin; van Duursen, Majorie; Burtey, Stéphane; Verhaar, Marianne C.; Meijers, Björn; Masereeuw, Rosalinde
(2019) Proceedings of the National Academy of Sciences of the United States of America, volume 116, issue 32, pp. 16105 - 16110
(Article)
Abstract
Membrane transporters and receptors are responsible for balancing nutrient and metabolite levels to aid body homeostasis. Here, we report that proximal tubule cells in kidneys sense elevated endogenous, gut microbiome-derived, metabolite levels through EGF receptors and downstream signaling to induce their secretion by up-regulating the organic anion transporter-1 (OAT1). Remote
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metabolite sensing and signaling was observed in kidneys from healthy volunteers and rats in vivo, leading to induced OAT1 expression and increased removal of indoxyl sulfate, a prototypical microbiome-derived metabolite and uremic toxin. Using 2D and 3D human proximal tubule cell models, we show that indoxyl sulfate induces OAT1 via AhR and EGFR signaling, controlled by miR-223. Concomitantly produced reactive oxygen species (ROS) control OAT1 activity and are balanced by the glutathione pathway, as confirmed by cellular metabolomic profiling. Collectively, we demonstrate remote metabolite sensing and signaling as an effective OAT1 regulation mechanism to maintain plasma metabolite levels by controlling their secretion.
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Keywords: Indoxyl sulfate, Kidney proximal tubule, Organic anion transporter 1, Remote sensing and signaling, General, Journal Article
ISSN: 0027-8424
Publisher: National Academy of Sciences
Note: Funding Information: ACKNOWLEDGMENTS. This study was supported by the European Renal Association–European Dialysis and Transplant Association (ERA-EDTA) endorsed Work Group EUTox. K.J. is supported by the “Future Medicines” research program, which is financed by the Netherlands Organisation for Scientific Research. E.N. is a recipient of a postdoctoral fellowship of the Research Foundation Flanders (FWO). R.P. is the recipient of a PhD fellowship of the FWO (Grant 11E9813N). B.M. received funding from the FWO Funding Information: This study was supported by the European Renal Association?European Dialysis and Transplant Association (ERA-EDTA) endorsed Work Group EUTox. K.J. is supported by the ?Future Medicines? research program, which is financed by the Netherlands Organisation for Scientific Research. E.N. is a recipient of a postdoctoral fellowship of the Research Foundation Flanders (FWO). R.P. is the recipient of a PhD fellowship of the FWO (Grant 11E9813N). B.M. received funding from the FWO (Grant G077514N) and Katholieke Universiteit Leuven (IDO/13/015). J.S. is supported by the European Research Council (Evicare #725229) and the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federations of University Medical Centers, The Netherlands Organization for Health Research and Development, and the Royal Netherlands Academy of Sciences. R.M. is supported by the Dutch Kidney Foundation (17OI13). The clinical trial was supported by the Dutch Ministry of Economic Affairs Program Topsector Agri & Food under Grant 15269: Sustainable Future Proteins?Focus on nutritional and health promoting quality. The views expressed in this manuscript are those of the authors and do not necessarily reflect the position or policy of funding organizations: Cargill, Lesaffre, PepsiCo, Badische Anilin- & Soda-Fabrik (BASF), Mimetas, Proti-Farm, Danone Nutricia Research, Quorn Foods, Darling Ingredients, Roquette, and Avebe. We thank Sandra Nijmeijer (Division of Toxicology and Veterinary Pharmacology, Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands), Igor Middel (Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University), and Henk van den Toorn and Bas van Breukelen (Biomolecular Mass Spectrometry and Proteomics and Utrecht Bioinformatics Center, Utrecht University) for technical assistance in the AhR reporter assay, mass spectrometry, and bioinformatics analysis, respectively. Funding Information: (Grant G077514N) and Katholieke Universiteit Leuven (IDO/13/015). J.S. is supported by the European Research Council (Evicare #725229) and the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federations of University Medical Centers, The Netherlands Organization for Health Research and Development, and the Royal Netherlands Academy of Sciences. R.M. is supported by the Dutch Kidney Foundation (17OI13). The clinical trial was supported by the Dutch Ministry of Economic Affairs Program Topsector Agri & Food under Grant 15269: Sustainable Future Proteins—Focus on nutritional and health promoting quality. The views expressed in this manuscript are those of the authors and do not necessarily reflect the position or policy of funding organizations: Cargill, Lesaffre, Publisher Copyright: © 2019 National Academy of Sciences. All rights reserved.
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