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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2019-08, Vol.116 (32), p.16105-16110
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Animals; Anions; Biological Sciences; Cell culture; Detection; Epidermal growth factor receptors; ErbB Receptors - metabolism; Gastrointestinal Microbiome; Glutathione; Glutathione - metabolism; Homeostasis; Humans; Intestinal microflora; Kidney Tubules, Proximal - metabolism; Kidneys; Life Sciences; Metabolome; Metabolomics; Microbiomes; Organic Anion Transport Protein 1 - metabolism; Proximal tubules; Rats; Reactive oxygen species; Reactive Oxygen Species - metabolism; Receptors; Receptors, Aryl Hydrocarbon - metabolism; Remote sensing; Secretion; Signal Transduction; Signaling; Sodium; Sulfates; Three dimensional models; Toxins; Two dimensional models
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1821809116

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.