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, and Rosalinde Masereeuw

Published: 06/08/2019


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.

Full Access Link: Proceedings of the National Academy of Sciences of the United States of America