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

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