Profiling of insulin-resistant kidney models and human biopsies reveals common and cell-type-specific mechanisms underpinning Diabetic Kidney Disease

Abigail C. Lay, Tran Van Du T., Viji Nair, Virginie Betin, Jennifer A. Hurcombe, Alexandra F. Barrington, Robert JP Pope, Frédéric Burdet, Florence Mehl, Dmytro Kryvokhyzha, Abrar Ahmad, Matthew C. Sinton, Philip Lewis, Marieangela C. Wilson, Rajasree Menon, Edgar Otto, Kate J. Heesom, Mark Ibberson, Helen C. Looker, Robert G. Nelson, Wenjun Ju, Matthias Kretzler, Simon C. Satchell, Maria F. Gomez and Richard J. M. Coward ()
Additional contact information
Abigail C. Lay: University of Bristol
Tran Van Du T.: SIB Swiss Institute of Bioinformatics
Viji Nair: University of Michigan
Virginie Betin: University of Bristol
Jennifer A. Hurcombe: University of Bristol
Alexandra F. Barrington: University of Bristol
Robert JP Pope: University of Bristol
Frédéric Burdet: SIB Swiss Institute of Bioinformatics
Florence Mehl: SIB Swiss Institute of Bioinformatics
Dmytro Kryvokhyzha: Lund University
Abrar Ahmad: Lund University
Matthew C. Sinton: University of Manchester
Philip Lewis: University of Bristol
Marieangela C. Wilson: University of Bristol
Rajasree Menon: University of Michigan
Edgar Otto: University of Michigan
Kate J. Heesom: University of Bristol
Mark Ibberson: SIB Swiss Institute of Bioinformatics
Helen C. Looker: National Institute of Health
Robert G. Nelson: National Institute of Health
Wenjun Ju: University of Michigan
Matthias Kretzler: University of Michigan
Simon C. Satchell: University of Bristol
Maria F. Gomez: Lund University
Richard J. M. Coward: University of Bristol

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract Diabetic kidney disease (DKD) is the leading cause of end stage kidney failure worldwide, of which cellular insulin resistance is a major driver. Here, we study key human kidney cell types implicated in DKD (podocytes, glomerular endothelial, mesangial and proximal tubular cells) in insulin sensitive and resistant conditions, and perform simultaneous transcriptomics and proteomics for integrated analysis. Our data is further compared with bulk- and single-cell transcriptomic kidney biopsy data from early- and advanced-stage DKD patient cohorts. We identify several consistent changes (individual genes, proteins, and molecular pathways) occurring across all insulin-resistant kidney cell types, together with cell-line-specific changes occurring in response to insulin resistance, which are replicated in DKD biopsies. This study provides a rich data resource to direct future studies in elucidating underlying kidney signalling pathways and potential therapeutic targets in DKD.

Date: 2024
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DOI: 10.1038/s41467-024-54089-1

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