Kidney Week

Abstract: FR-PO361

Integrative Transcriptome and Proteome Profiling of Insulin-Resistant Kidney Cell Models and Patient Biopsies Reveals Common and Cell Type-Specific Mechanisms Underpinning Diabetic Kidney Disease

Session Information

• Diabetic Kidney Disease: Basic - I
  November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Diabetic Kidney Disease

• 701 Diabetic Kidney Disease: Basic

Authors

• Coward, Richard, University of Bristol, Bristol, Bristol, United Kingdom

Richard Coward,

• Lay, Abigail Charlotte, University of Bristol, Bristol, Bristol, United Kingdom

Abigail Charlotte Lay,

• Tran, Van Du Thuong, Swiss Institute of Bioinformatics, Lausanne, Vaud, Switzerland

Van Du Thuong Tran,

• Nair, Viji, University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States

Viji Nair,

• Betin, Virginie M. S., University of Bristol, Bristol, Bristol, United Kingdom

Virginie M. S. Betin,

• Burdet, Frédéric, Swiss Institute of Bioinformatics, Lausanne, Vaud, Switzerland

Frédéric Burdet,

• Mehl, Florence, Swiss Institute of Bioinformatics, Lausanne, Vaud, Switzerland

Florence Mehl,

• Kryvokhyzha, Dmytro, Lunds Universitet, Lund, Sweden

Dmytro Kryvokhyzha,

• Ahmad, Abrar, Lunds Universitet, Lund, Sweden

Abrar Ahmad,

• Lewis, Philip Alexander, University of Bristol, Bristol, Bristol, United Kingdom

Philip Alexander Lewis,

• Wilson, Marieangela C., University of Bristol, Bristol, Bristol, United Kingdom

Marieangela C. Wilson,

• Menon, Rajasree, University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States

Rajasree Menon,

• Otto, Edgar A., University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States

Edgar A. Otto,

• Heesom, Kate J., University of Bristol, Bristol, Bristol, United Kingdom

Kate J. Heesom,

• Looker, Helen C., National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona, United States

Helen C. Looker,

• Nelson, Robert G., National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona, United States

Robert G. Nelson,

• Ju, Wenjun, University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States

Wenjun Ju,

• Kretzler, Matthias, University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States

Matthias Kretzler,

• Satchell, Simon C., University of Bristol, Bristol, Bristol, United Kingdom

Simon C. Satchell,

• Gomez, Maria F., Lunds Universitet, Lund, Sweden

Maria F. Gomez,

Background

Diabetic kidney disease (DKD) is the leading cause of end stage kidney failure worldwide. It is now clear that cellular insulin resistance is a major driver of this disease.

Methods

Using established human conditionally immortalised podocytes (Pods), glomerular endothelial cells (GECs), mesangial cells (MCs), and proximal tubular cells (PTCs), we modelled both insulin sensitivity and insulin resistance and performed simultaneous transcriptomics and proteomics for integrated analysis. Our data was further compared with bulk- and single-cell transcriptomic kidney biopsy data from early- and advanced-stage DKD patient cohorts.

Results

We identified several consistent changes (individual genes, proteins, and molecular pathways) occurring across all insulin-resistant kidney cell types, which were replicated in human early- and/or advanced-stage DKD biopsies. These included the genes CTSS, NRBF2, C3, CXCL1, TFPI2 and PFKFB3, and pathways related to the inflammatory response, ER stress and glycoprotein metabolism. We further identified several cell-line-specific molecular changes occurring in response to insulin resistance, which were replicated in single-cell sequencing data from DKD, together with a selective reduction in mitochondrial function in Pods, MCs and PTC, but not GECs.

Conclusion

This study provides a rich data resource to direct future studies in elucidating underlying kidney signalling pathways and potential therapeutic targets in DKD.

Funding

• Government Support – Non-U.S.