Proteomic and transcriptomic profiling reveal different aspects of aging in the kidney

  1. Yuka Takemon
  2. Joel M Chick
  3. Isabela Gerdes Gyuricza
  4. Daniel A Skelly
  5. Olivier Devuyst
  6. Steven P Gygi
  7. Gary A Churchill
  8. Ron Korstanje  Is a corresponding author
  1. The Jackson Laboratory, United States
  2. Vividion Therapeutics, United States
  3. University of Zurich, Switzerland
  4. Harvard Medical School, United States

Abstract

Little is known about the molecular changes that take place in the kidney during the aging process. In order to better understand these changes, we measured mRNA and protein levels in genetically diverse mice at different ages. We observed distinctive change in mRNA and protein levels as a function of age. Changes in both mRNA and protein are associated with increased immune infiltration and decreases in mitochondrial function. Proteins show a greater extent of change and reveal changes in a wide array of biological processes including unique, organ-specific features of aging in kidney. Most importantly, we observed functionally important age-related changes in protein that occur in the absence of corresponding changes in mRNA. Our findings suggest that mRNA profiling alone provides an incomplete picture of molecular aging in the kidney and that examination of changes in proteins is essential to understand aging processes that are not transcriptionally regulated.

Data availability

Source data and analysis scripts have been deposited with FigShare (10.6084/m9.figshare. 12894146). In addition, the transcript and protein data are available in an online tool that supports genetic mapping analysis (https://churchilllab.jax.org/qtlviewer/JAC/DOKidney).The RNA-seq data have been deposited in NCBI's Gene Expression Omnibus, accession number GSE121330 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE121330). The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD023823.

The following data sets were generated

Article and author information

Author details

  1. Yuka Takemon

    The Jackson Laboratory, Bar Harbor, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3538-4409
  2. Joel M Chick

    Proteomics, Vividion Therapeutics, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Isabela Gerdes Gyuricza

    The Jackson Laboratory, Bar Harbor, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7969-1910
  4. Daniel A Skelly

    The Jackson Laboratory, Bar Harbor, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2329-2216
  5. Olivier Devuyst

    Institute of Physiology, Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3744-4767
  6. Steven P Gygi

    Department of Cell Biology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Gary A Churchill

    The Jackson Laboratory, Bar Harbor, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9190-9284
  8. Ron Korstanje

    The Jackson Laboratory, Bar Harbor, United States
    For correspondence
    Ron.Korstanje@jax.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2808-1610

Funding

National Institutes of Health (AG038070)

  • Ron Korstanje

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

Ethics

Animal experimentation: The Jackson Laboratory's Institutional Animal Care and Use Committee approved all reported mouse studies.(AUS#06005).

Reviewing Editor

  1. Jing-Dong Jackie Han, Chinese Academy of Sciences, China

Version history

  1. Received: September 1, 2020
  2. Accepted: March 6, 2021
  3. Accepted Manuscript published: March 9, 2021 (version 1)
  4. Version of Record published: May 4, 2021 (version 2)
  5. Version of Record updated: February 2, 2022 (version 3)

Copyright

© 2021, Takemon 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

  • 7,197
    Page views
  • 872
    Downloads
  • 39
    Citations

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

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. Yuka Takemon
  2. Joel M Chick
  3. Isabela Gerdes Gyuricza
  4. Daniel A Skelly
  5. Olivier Devuyst
  6. Steven P Gygi
  7. Gary A Churchill
  8. Ron Korstanje
(2021)
Proteomic and transcriptomic profiling reveal different aspects of aging in the kidney
eLife 10:e62585.
https://doi.org/10.7554/eLife.62585

Further reading

    1. Computational and Systems Biology
    Louis Gall, Carrie Duckworth ... Carmen Pin
    Research Article

    The maintenance of the functional integrity of the intestinal epithelium requires a tight coordination between cell production, migration and shedding along the crypt-villus axis. Dysregulation of these processes may result in loss of the intestinal barrier and disease. With the aim of generating a more complete and integrated understanding of how the epithelium maintains homeostasis and recovers after injury, we have built a multi-scale agent-based model (ABM) of the mouse intestinal epithelium. We demonstrate that stable, self-organizing behaviour in the crypt emerges from the dynamic interaction of multiple signalling pathways, such as Wnt, Notch, BMP, ZNRF3/RNF43 and YAP-Hippo pathways, which regulate proliferation and differentiation, respond to environmental mechanical cues, form feedback mechanisms and modulate the dynamics of the cell cycle protein network. The model recapitulates the crypt phenotype reported after persistent stem cell ablation and after the inhibition of the CDK1 cycle protein. Moreover, we simulated 5-fluorouracil (5-FU)-induced toxicity at multiple scales starting from DNA and RNA damage, which disrupts the cell cycle, cell signalling, proliferation, differentiation and migration and leads to loss of barrier integrity. During recovery, our in-silico crypt regenerates its structure in a self-organizing, dynamic fashion driven by dedifferentiation and enhanced by negative feedback loops. Thus, the model enables the simulation of xenobiotic-, in particular chemotherapy-, induced mechanisms of intestinal toxicity and epithelial recovery. Overall, we present a systems model able to simulate the disruption of molecular events and its impact across multiple levels of epithelial organization and demonstrate its application to epithelial research and drug development.

    1. Computational and Systems Biology
    Arya Mani
    Insight

    A deep analysis of multiple genomic datasets reveals which genetic pathways associated with atherosclerosis and coronary artery disease are shared between mice and humans.