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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 prototyp-ical 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. kidney proximal tubule | organic anion transporter 1 | remote sensing and signaling | indoxyl sulfate
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Jitske Jansen, Katja Jansen, Ellen Neven, Ruben Poesen, Amr Othman, et al.. 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 , National Academy of Sciences, 2019, 116 (32), pp.16105-16110. ⟨10.1073/pnas.1821809116⟩. ⟨hal-02544279⟩

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