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

• Published in: Nature communications 2024-11, Vol.15 (1), p.10018-19, Article 10018
• Main Authors: Lay, Abigail C., Tran, Van Du T., Nair, Viji, Betin, Virginie, Hurcombe, Jennifer A., Barrington, Alexandra F., Pope, Robert JP, Burdet, Frédéric, Mehl, Florence, Kryvokhyzha, Dmytro, Ahmad, Abrar, Sinton, Matthew C., Lewis, Philip, Wilson, Marieangela C., Menon, Rajasree, Otto, Edgar, Heesom, Kate J., Ibberson, Mark, Looker, Helen C., Nelson, Robert G., Ju, Wenjun, Kretzler, Matthias, Satchell, Simon C., Gomez, Maria F., Coward, Richard J. M.
• Format: Article
• Language: English
• Subjects: 13; 13/106; 38/79; 49/91; 692/163/2743; 692/4022/1585; Biomarkers; Biopsy; Cell culture; Diabetes; Diabetes mellitus; Diabetic Nephropathies - metabolism; Diabetic Nephropathies - pathology; Disease resistance; Gene Expression Profiling; Humanities and Social Sciences; Humans; Insulin; Insulin Resistance; Kidney - metabolism; Kidney - pathology; Kidney diseases; Kidneys; multidisciplinary; Proteomics; Renal failure; Science; Science (multidisciplinary); Signal Transduction; Therapeutic targets; Transcriptome; Transcriptomics
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-54089-1

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. Diabetic kidney disease is the leading cause of kidney failure in the world and cellular insulin resistance is an important driver of this disease. Here, Lay et al identify multiple insulin-resistance driven “common” and “cell-specific” kidney cell pathways and molecules that may be good therapeutic and biomarker targets.