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 journalArticleAcademicpeer-review

3 Citations (Scopus)

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 languageEnglish
Pages (from-to)16105-16110
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number32
DOIs
Publication statusPublished - 6 Aug 2019

Fingerprint

Organic Anion Transporters
Proximal Kidney Tubule
Anions
Indican
Kidney
Metabolomics
Membrane Transport Proteins
Microbiota
Glutathione
Reactive Oxygen Species
Healthy Volunteers
Homeostasis
Gastrointestinal Microbiome
Food

Keywords

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

Cite this

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. / Remote sensing and signaling in kidney proximal tubules stimulates gut microbiome-derived organic anion secretion. In: Proceedings of the National Academy of Sciences of the United States of America. 2019 ; Vol. 116, No. 32. pp. 16105-16110.
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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 = "8",
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doi = "10.1073/pnas.1821809116",
language = "English",
volume = "116",
pages = "16105--16110",
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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, 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; 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.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 32, 06.08.2019, p. 16105-16110.

Research output: Contribution to journalArticleAcademicpeer-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

U2 - 10.1073/pnas.1821809116

DO - 10.1073/pnas.1821809116

M3 - Article

VL - 116

SP - 16105

EP - 16110

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 32

ER -