Reducing lipid bilayer stress by monounsaturated fatty acids protects renal proximal tubules in diabetes

  1. Albert Pérez-Martí
  2. Suresh Ramakrishnan
  3. Jiayi Li
  4. Aurelien Dugourd
  5. Martijn R Molenaar
  6. Luigi R De La Motte
  7. Kelli Grand
  8. Anis Mansouri
  9. Mélanie Parisot
  10. Soeren S Lienkamp
  11. Julio Saez-Rodriguez
  12. Matias Simons  Is a corresponding author
  1. University Hospital Heidelberg, Germany
  2. Heidelberg University, Germany
  3. European Molecular Biology Laboratorium (EMBL), Germany
  4. University of Zurich, Switzerland
  5. INSERM U1163, INSERM US24/CNRS UMS3633, Paris Descartes Sorbonne Paris Cite University, France

Abstract

In diabetic patients, dyslipidemia frequently contributes to organ damage such as diabetic kidney disease (DKD). Dyslipidemia is associated with both excessive deposition of triacylglycerol (TAG) in lipid droplets (LD) and lipotoxicity. Yet, it is unclear how these two effects correlate with each other in the kidney and how they are influenced by dietary patterns. By using a diabetes mouse model, we find here that high fat diet enriched in the monounsaturated oleic acid (OA) caused more lipid storage in LDs in renal proximal tubular cells (PTC) but less tubular damage than a corresponding butter diet with the saturated palmitic acid (PA). This effect was particularly evident S2/S3 but not S1 segments of the proximal tubule. Combining transcriptomics, lipidomics and functional studies, we identify endoplasmic reticulum (ER) stress as the main cause of PA-induced PTC injury. Mechanistically, ER stress is caused by elevated levels of saturated TAG precursors, reduced LD formation and, consequently, higher membrane order in the ER. Simultaneous addition of OA rescues the cytotoxic effects by normalizing membrane order and by increasing both TAG and LD formation. Our study thus emphasizes the importance of monounsaturated fatty acids for the dietary management of DKD by preventing lipid bilayer stress in the ER and promoting TAG and LD formation in PTCs.

Data availability

- iRECs lipidomic data have been deposited in Dryadhttps://doi.org/10.5061/dryad.x95x69pm1.- Kidney cortex of diabetic mice lipidomic data have been deposited in Dryadhttps://doi.org/10.5061/dryad.qv9s4mwgx.- iRECs Transcriptome raw data (bam files) can be found at https://www.ncbi.nlm.nih.gov/sra/PRJNA809508- iRECs Transcriptome processed data (FPKM and DEG) have been deposited in DryadDOI https://doi.org/10.5061/dryad.gqnk98sq7-The full code for the TF activity-lipid correlation analysis can be found in: https://github.com/saezlab/Albert_perez_RNA_lipid/tree/main/scripts

The following data sets were generated

Article and author information

Author details

  1. Albert Pérez-Martí

    Division of Nephrogenetics, University Hospital Heidelberg, Heidelberg, Germany
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3234-3756
  2. Suresh Ramakrishnan

    Division of Nephrogenetics, University Hospital Heidelberg, Heidelberg, Germany
    Competing interests
    No competing interests declared.
  3. Jiayi Li

    Division of Nephrogenetics, University Hospital Heidelberg, Heidelberg, Germany
    Competing interests
    No competing interests declared.
  4. Aurelien Dugourd

    Faculty of Medicine, Heidelberg University, Heidelberg, Germany
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0714-028X
  5. Martijn R Molenaar

    Structural and Computational Biology Unit, European Molecular Biology Laboratorium (EMBL), Heidelberg, Germany
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5221-608X
  6. Luigi R De La Motte

    Division of Nephrogenetics, University Hospital Heidelberg, Heidelberg, Germany
    Competing interests
    No competing interests declared.
  7. Kelli Grand

    Institute of Anatomy, University of Zurich, Zurich, Switzerland
    Competing interests
    No competing interests declared.
  8. Anis Mansouri

    Faculty of Medicine, Heidelberg University, Heidelberg, Germany
    Competing interests
    No competing interests declared.
  9. Mélanie Parisot

    Genomics Core Facility, Institut Imagine-Structure Fédérative de Recherche Necker, INSERM U1163, INSERM US24/CNRS UMS3633, Paris Descartes Sorbonne Paris Cite University, Paris, France
    Competing interests
    No competing interests declared.
  10. Soeren S Lienkamp

    Institute of Anatomy, University of Zurich, Zurich, Switzerland
    Competing interests
    No competing interests declared.
  11. Julio Saez-Rodriguez

    Faculty of Medicine, Heidelberg University, Heidelberg, Germany
    Competing interests
    Julio Saez-Rodriguez, has received funding from GSK and Sanofi and consultant fees from Travere Therapeutics..
  12. Matias Simons

    Division of Nephrogenetics, University Hospital Heidelberg, Heidelberg, Germany
    For correspondence
    matias.simons@med.uni-heidelberg.de
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3959-6350

Funding

European Research Council (865408)

  • Jiayi Li

Novo Nordisk Foundation Center for Basic Metabolic Research (NNF18OC0052457)

  • Suresh Ramakrishnan

Deutsche Forschungsgemeinschaft (DFG SI1303/5-1)

  • Matias Simons

European Research Council (804474)

  • Kelli Grand

Swiss National Centre of Competence in Research Kidney Control of Homeostasis (310030_189102)

  • Soeren S Lienkamp

Fondation pour la Recherche Médicale (SPF20170938629)

  • Albert Pérez-Martí

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All of the experimental protocols in this study were performed with the approval of the animal experimentation ethics committee of the University Paris Descartes (CEEA 34), projects registered as 17-058 and 20-022

Reviewing Editor

  1. Raymond Harris

Publication history

  1. Received: October 1, 2021
  2. Accepted: May 11, 2022
  3. Accepted Manuscript published: May 12, 2022 (version 1)

Copyright

© 2022, Pérez-Martí et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Albert Pérez-Martí
  2. Suresh Ramakrishnan
  3. Jiayi Li
  4. Aurelien Dugourd
  5. Martijn R Molenaar
  6. Luigi R De La Motte
  7. Kelli Grand
  8. Anis Mansouri
  9. Mélanie Parisot
  10. Soeren S Lienkamp
  11. Julio Saez-Rodriguez
  12. Matias Simons
(2022)
Reducing lipid bilayer stress by monounsaturated fatty acids protects renal proximal tubules in diabetes
eLife 11:e74391.
https://doi.org/10.7554/eLife.74391

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