1. Cell Biology

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
https://doi.org/10.7554/eLife.74391
Share this article
Cite this article
  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
  2. Download BibTeX
  3. Download .RIS

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.

Reviewing Editor

  1. Raymond Harris

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

Version history

  1. Preprint posted: September 10, 2021 (view preprint)
  2. Received: October 1, 2021
  3. Accepted: May 11, 2022
  4. Accepted Manuscript published: May 12, 2022 (version 1)
  5. Version of Record published: May 31, 2022 (version 2)

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.

Metrics

  • 2,306
    Page views
  • 624
    Downloads
  • 14
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Share this article

https://doi.org/10.7554/eLife.74391

Categories and tags

Research organism

Further reading

    1. Cell Biology
    2. Chromosomes and Gene Expression

    Heat stress impairs centromere structure and segregation of meiotic chromosomes in Arabidopsis

    Lucie Crhak Khaitova, Pavlina Mikulkova ... Karel Riha
    Research Article

    Heat stress is a major threat to global crop production, and understanding its impact on plant fertility is crucial for developing climate-resilient crops. Despite the known negative effects of heat stress on plant reproduction, the underlying molecular mechanisms remain poorly understood. Here, we investigated the impact of elevated temperature on centromere structure and chromosome segregation during meiosis in Arabidopsis thaliana. Consistent with previous studies, heat stress leads to a decline in fertility and micronuclei formation in pollen mother cells. Our results reveal that elevated temperature causes a decrease in the amount of centromeric histone and the kinetochore protein BMF1 at meiotic centromeres with increasing temperature. Furthermore, we show that heat stress increases the duration of meiotic divisions and prolongs the activity of the spindle assembly checkpoint during meiosis I, indicating an impaired efficiency of the kinetochore attachments to spindle microtubules. Our analysis of mutants with reduced levels of centromeric histone suggests that weakened centromeres sensitize plants to elevated temperature, resulting in meiotic defects and reduced fertility even at moderate temperatures. These results indicate that the structure and functionality of meiotic centromeres in Arabidopsis are highly sensitive to heat stress, and suggest that centromeres and kinetochores may represent a critical bottleneck in plant adaptation to increasing temperatures.

    1. Cell Biology

    High-altitude hypoxia exposure inhibits erythrophagocytosis by inducing macrophage ferroptosis in the spleen

    Wan-ping Yang, Mei-qi Li ... Qian-qian Luo
    Research Article

    High-altitude polycythemia (HAPC) affects individuals living at high altitudes, characterized by increased red blood cells (RBCs) production in response to hypoxic conditions. The exact mechanisms behind HAPC are not fully understood. We utilized a mouse model exposed to hypobaric hypoxia (HH), replicating the environmental conditions experienced at 6000 m above sea level, coupled with in vitro analysis of primary splenic macrophages under 1% O2 to investigate these mechanisms. Our findings indicate that HH significantly boosts erythropoiesis, leading to erythrocytosis and splenic changes, including initial contraction to splenomegaly over 14 days. A notable decrease in red pulp macrophages (RPMs) in the spleen, essential for RBCs processing, was observed, correlating with increased iron release and signs of ferroptosis. Prolonged exposure to hypoxia further exacerbated these effects, mirrored in human peripheral blood mononuclear cells. Single-cell sequencing showed a marked reduction in macrophage populations, affecting the spleen’s ability to clear RBCs and contributing to splenomegaly. Our findings suggest splenic ferroptosis contributes to decreased RPMs, affecting erythrophagocytosis and potentially fostering continuous RBCs production in HAPC. These insights could guide the development of targeted therapies for HAPC, emphasizing the importance of splenic macrophages in disease pathology.

    1. Cell Biology

    Golgi Apparatus: Making progress

    Jurgen Denecke
    Insight

    Mapping proteins in and associated with the Golgi apparatus reveals how this cellular compartment emerges in budding yeast and progresses over time.