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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 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.

SUBMITTER: Jansen J

PROVIDER: S-EPMC6689987 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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

Jansen Jitske J Jansen Katja K Neven Ellen E Poesen Ruben R Othman Amr A van Mil Alain A Sluijter Joost J Sastre Torano Javier J Zaal Esther A EA Berkers Celia R CR Esser Diederik D Wichers Harry J HJ van Ede Karin K van Duursen Majorie M Burtey Stéphane S Verhaar Marianne C MC Meijers Björn B Masereeuw Rosalinde R

Proceedings of the National Academy of Sciences of the United States of America 20190724 32

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 ...[more]

PMID: 31341083

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Project description:Organic anion transporters (OATs, SLC22) interact with a remarkably diverse array of endogenous and exogenous organic anions. However, little is known about the structural features that determine their substrate selectivity. We examined the substrate binding preferences and transport function of olfactory organic anion transporter, Oat6, in comparison with the more broadly expressed transporter, Oat1 (first identified as NKT). In analyzing interactions of both transporters with over 40 structurally diverse organic anions, we find a correlation between organic anion potency (pKi) and hydrophobicity (logP) suggesting a hydrophobicity-driven association with transporter-binding sites, which appears particularly prominent for Oat6. On the other hand, organic anion binding selectivity between Oat6 and Oat1 is influenced by the anion mass and net charge. Smaller mono-anions manifest greater potency for Oat6 and di-anions for Oat1. Comparative molecular field analysis confirms these mechanistic insights and provides a model for predicting new OAT substrates. By comparative molecular field analysis, both hydrophobic and charged interactions contribute to Oat1 binding, although it is predominantly the former that contributes to Oat6 binding. Together, the data suggest that, although the three-dimensional structures of these two transporters may be very similar, the binding pockets exhibit crucial differences. Furthermore, for six radiolabeled substrates, we assessed transport efficacy (Vmax) for Oat6 and Oat1. Binding potency and transport efficacy had little correlation, suggesting that different molecular interactions are involved in substrate binding to the transporter and translocation across the membrane. Substrate specificity for a particular transporter may enable design of drugs for targeting to specific tissues (e.g. olfactory mucosa). We also discuss how these data suggest a possible mechanism for remote sensing between OATs in different tissue compartments (e.g. kidney, olfactory mucosa) via organic anions.

Project description:Developing an efficient and sustainable precision irrigation strategy is crucial in contemporary agriculture. This study aimed to combine proximal and remote sensing techniques to show the benefits of using both monitoring methods, simultaneously assessing the water status and response of 'Calatina' olive under two distinct irrigation levels: full irrigation (FI), and drought stress (DS, -3 to -4 MPa). Stem water potential (Ψstem) and stomatal conductance (gs) were monitored weekly as reference indicators of plant water status. Crop water stress index (CWSI) and stomatal conductance index (Ig) were calculated through ground-based infrared thermography. Fruit gauges were used to monitor continuously fruit growth and data were converted in fruit daily weight fluctuations (ΔW) and relative growth rate (RGR). Normalized difference vegetation index (NDVI), normalized difference RedEdge index (NDRE), green normalized difference vegetation index (GNDVI), chlorophyll vegetation index (CVI), modified soil-adjusted vegetation index (MSAVI), water index (WI), normalized difference greenness index (NDGI) and green index (GI) were calculated from data collected by UAV-mounted multispectral camera. Data obtained from proximal sensing were correlated with both Ψstem and gs, while remote sensing data were correlated only with Ψstem. Regression analysis showed that both CWSI and Ig proved to be reliable indicators of Ψstem and gs. Of the two fruit growth parameters, ΔW exhibited a stronger relationship, primarily with Ψstem. Finally, NDVI, GNDVI, WI and NDRE emerged as the vegetation indices that correlated most strongly with Ψstem, achieving high R2 values. Combining proximal and remote sensing indices suggested two valid approaches: a more simplified one involving the use of CWSI and either NDVI or WI, and a more comprehensive one involving CWSI and ΔW as proximal indices, along with WI as a multispectral index. Further studies on combining proximal and remote sensing data will be necessary in order to find strategic combinations of sensors and establish intervention thresholds.

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Dataset Information

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

Publications

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

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