Remote sensing and signaling in kidney proximal tubules stimulates gut microbiome-derived organic anion secretion

Jitske Jansen; Katja Jansen; Ellen Neven; Ruben Poesen; Amr Othman; Alain van Mil; Joost Sluijter; Javier Sastre Torano; Esther A. Zaal; Celia R. Berkers; Diederik Esser; Harry J. Wichers; Karin van Ede; Majorie van Duursen; Stéphane Burtey; Marianne C. Verhaar; Björn Meijers; Rosalinde Masereeuw

doi:10.1073/pnas.1821809116

Remote sensing and signaling in kidney proximal tubules stimulates gut microbiome-derived organic anion secretion

Jitske Jansen
, Katja Jansen
, Ellen Neven
, Ruben Poesen
, Amr Othman
, Alain van Mil
, Joost Sluijter
, Javier Sastre Torano
, Esther A. Zaal
, Celia R. Berkers
, Diederik Esser
, Harry J. Wichers
, Karin van Ede
, Majorie van Duursen
, Stéphane Burtey
, Marianne C. Verhaar
, Björn Meijers
, Rosalinde Masereeuw^*

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

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 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.

Original language	English
Pages (from-to)	16105-16110
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America (PNAS)
Volume	116
Issue number	32
DOIs	https://doi.org/10.1073/pnas.1821809116
Publication status	Published - 6 Aug 2019
Externally published	Yes

Funding

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 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. (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,

Funders	Funder number
Dutch Federations of University Medical Centers
Dutch Ministry of Economic Affairs Program Topsector Agri & Food	15269
European Dialysis and Transplant Association
European Renal Association
European Renal Association?European Dialysis and Transplant Association
Netherlands CardioVascular Research Initiative
Netherlands Organization for Health Research and Development
Royal Netherlands Academy of Sciences
Utrecht Institute for Pharmaceutical Sciences
Cargill
PepsiCo	BASF
Danone Research Centre for Specialised Nutrition
Horizon 2020 Framework Programme	725229
European Research Council
Royal Swedish Academy of Sciences
ZonMw
Universiteit Utrecht
Hartstichting
Nierstichting	17OI13
Fonds Wetenschappelijk Onderzoek	11E9813N
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
KU Leuven	IDO/13/015
European Renal Association-European Dialysis and Transplant Association

Keywords

Indoxyl sulfate
Kidney proximal tubule
Organic anion transporter 1
Remote sensing and signaling

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10.1073/pnas.1821809116

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Jansen, J., Jansen, K., Neven, E., Poesen, R., Othman, A., van Mil, A., Sluijter, J., Torano, J. S., Zaal, E. A., Berkers, C. R., Esser, D., Wichers, H. J., van Ede, K., van Duursen, M., Burtey, S., Verhaar, M. C., Meijers, B., & Masereeuw, R. (2019). Remote sensing and signaling in kidney proximal tubules stimulates gut microbiome-derived organic anion secretion. Proceedings of the National Academy of Sciences of the United States of America (PNAS), 116(32), 16105-16110. https://doi.org/10.1073/pnas.1821809116

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title = "Remote sensing and signaling in kidney proximal tubules stimulates gut microbiome-derived organic anion secretion",

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 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.",

keywords = "Indoxyl sulfate, Kidney proximal tubule, Organic anion transporter 1, Remote sensing and signaling",

author = "Jitske Jansen and Katja Jansen and Ellen Neven and Ruben Poesen and Amr Othman and \{van Mil\}, Alain and Joost Sluijter and Torano, \{Javier Sastre\} and Zaal, \{Esther A.\} and Berkers, \{Celia R.\} and Diederik Esser and Wichers, \{Harry J.\} and \{van Ede\}, Karin and \{van Duursen\}, Majorie and St{\'e}phane Burtey and Verhaar, \{Marianne C.\} and Bj{\"o}rn Meijers and Rosalinde Masereeuw",

year = "2019",

month = aug,

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doi = "10.1073/pnas.1821809116",

language = "English",

volume = "116",

pages = "16105--16110",

journal = "Proceedings of the National Academy of Sciences of the United States of America (PNAS)",

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Jansen, J, Jansen, K, Neven, E, Poesen, R, Othman, A, van Mil, A, Sluijter, J, Torano, JS, Zaal, EA, Berkers, CR, Esser, D, Wichers, HJ, van Ede, K, van Duursen, M, Burtey, S, Verhaar, MC, Meijers, B & Masereeuw, R 2019, 'Remote sensing and signaling in kidney proximal tubules stimulates gut microbiome-derived organic anion secretion', Proceedings of the National Academy of Sciences of the United States of America (PNAS), vol. 116, no. 32, pp. 16105-16110. https://doi.org/10.1073/pnas.1821809116

Remote sensing and signaling in kidney proximal tubules stimulates gut microbiome-derived organic anion secretion. / Jansen, Jitske; Jansen, Katja; Neven, Ellen et al.
In: Proceedings of the National Academy of Sciences of the United States of America (PNAS), Vol. 116, No. 32, 06.08.2019, p. 16105-16110.

Research output: Contribution to Journal › Article › Academic › peer-review

TY - JOUR

T1 - Remote sensing and signaling in kidney proximal tubules stimulates gut microbiome-derived organic anion secretion

AU - Jansen, Jitske

AU - Jansen, Katja

AU - Neven, Ellen

AU - Poesen, Ruben

AU - Othman, Amr

AU - van Mil, Alain

AU - Sluijter, Joost

AU - Torano, Javier Sastre

AU - Zaal, Esther A.

AU - Berkers, Celia R.

AU - Esser, Diederik

AU - Wichers, Harry J.

AU - van Ede, Karin

AU - van Duursen, Majorie

AU - Burtey, Stéphane

AU - Verhaar, Marianne C.

AU - Meijers, Björn

AU - Masereeuw, Rosalinde

PY - 2019/8/6

Y1 - 2019/8/6

N2 - 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 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.

AB - 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 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.

KW - Indoxyl sulfate

KW - Kidney proximal tubule

KW - Organic anion transporter 1

KW - Remote sensing and signaling

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U2 - 10.1073/pnas.1821809116

DO - 10.1073/pnas.1821809116

M3 - Article

C2 - 31341083

AN - SCOPUS:85070219880

SN - 0027-8424

VL - 116

SP - 16105

EP - 16110

JO - Proceedings of the National Academy of Sciences of the United States of America (PNAS)

JF - Proceedings of the National Academy of Sciences of the United States of America (PNAS)

IS - 32

ER -

Remote sensing and signaling in kidney proximal tubules stimulates gut microbiome-derived organic anion secretion

Abstract

Funding

Keywords

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