Perifusate metabolomics interrogates nutrient exposure and oxidative stress response in kidney tubules

Cell Reports, vol. 45, pp. 117963

Abstract

Understanding metabolism at the organ level is challenging, as tissue metabolite signals are transient and reflect transport, metabolism, and inter-organ communication. Here, we address this challenge by using a perifusion platform that enables time-resolved metabolite measurements in living kidney tissue under controlled input conditions. We apply this approach to native tubule and glomerulus preparations and generate >45,000 longitudinal, time-resolved metabolite measurements using targeted metabolomics. Tubules release tricarboxylic acid cycle and acetylated amino acid intermediates and show dynamic metabolic rewiring under oxidative stress. Amino acid exposure rapidly activates antioxidative and urea cycle reactions, improving resistance to oxidative damage in a sex-dependent manner. Supporting the translational relevance, metabolites released from tubules upon oxidative stress are also found in plasma from humans with acute kidney injury (secondary analyses of the original clinical trial NCT01534364). Thus, the approach developed here enables time-resolved interrogation of renal metabolic responses with defined metabolite inputs.

Authors 19

1. Vera Christine Wulfmeyer corresponding

   Aarhus University

   Affiliation as printed

   Department of Biomedicine, Aarhus University, Aarhus, Denmark. Electronic address: wulfmeyer.vera@biomed.au.dk

2. Marlon Gernemann

   Aarhus University

   Affiliation as printed

   Department of Biomedicine, Aarhus University, Aarhus, Denmark

3. Xavier de la Rosa

   Aarhus University

   Affiliation as printed

   Department of Biomedicine, Aarhus University, Aarhus, Denmark

4. Anders Meldgaard Kristensen

   Aarhus University

   Affiliation as printed

   Department of Biomedicine, Aarhus University, Aarhus, Denmark

5. Peder Berg

   Aarhus University

   Affiliation as printed

   Department of Biomedicine, Aarhus University, Aarhus, Denmark

6. Lingyun Xiong

   University of California, Los Angeles

   Affiliation as printed

   Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, USA

7. Oliver Kretz

   University Medical Center Hamburg-Eppendorf

   Affiliation as printed

   III. Department of Medicine, University Hospital Hamburg-Eppendorf, Hamburg, Germany; Hamburg Center for Kidney Health (HCKH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Core Facility für Electron Microscopy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

8. Imke A.K. Fiedler

   University Medical Center Hamburg-Eppendorf

   Affiliation as printed

   Core Facility für Electron Microscopy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

9. Johannes Jaegers

   Aarhus University

   Affiliation as printed

   Department of Biomedicine, Aarhus University, Aarhus, Denmark

10. Anja M. Billing

    Aarhus University

    Affiliation as printed

    Department of Biomedicine, Aarhus University, Aarhus, Denmark

11. Nikolaj Bøgh

    Aarhus University

    Affiliation as printed

    Department of Clinical Medicine, MR Research Centre, Aarhus University, Aarhus, Denmark

12. Johanna Hoyer-Allo

    University of Cologne · University Hospital Cologne

    Affiliation as printed

    Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany

13. Franziska Grundmann

    University of Cologne · University Hospital Cologne

    Affiliation as printed

    Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany

14. Volker Rolf Burst

    University of Cologne · University Hospital Cologne

    Affiliation as printed

    Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; Emergency Department, University Hospital Cologne, Cologne, Germany

15. Christoffer Laustsen

    Aarhus University

    Affiliation as printed

    Department of Clinical Medicine, MR Research Centre, Aarhus University, Aarhus, Denmark

16. Ina Maria Schießl Aachen Department of Medicine 2

    Aarhus University · RWTH Aachen University

    Affiliation as printed

    Department of Biomedicine, Aarhus University, Aarhus, Denmark; Department of Medicine 2, RWTH Aachen University, Aachen, Germany

17. Roman‐Ulrich Müller Aachen Center of Excellence in Nephrology

    Düsseldorf University Hospital · Universitätsklinikum Aachen · Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases · Heinrich Heine University Düsseldorf

    Affiliation as printed

    Department of Nephrology, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany; Center of Excellence in Nephrology, University Hospitals Aachen, Cologne, Dusseldorf, North Rhine-Westphalia, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany

18. Fatih Demir

    Aarhus University

    Affiliation as printed

    Department of Biomedicine, Aarhus University, Aarhus, Denmark

19. Markus Matthias Rinschen corresponding

    Aarhus University · University Medical Center Hamburg-Eppendorf

    Affiliation as printed

    Department of Biomedicine, Aarhus University, Aarhus, Denmark; III. Department of Medicine, University Hospital Hamburg-Eppendorf, Hamburg, Germany; Hamburg Center for Kidney Health (HCKH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address: rinschen@biomed.au.dk