Spatially Localized Mesangial Cell Communication in Diabetic Kidney Disease

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Background: Substantial knowledge has been gained regarding podocyte injury in diabetic kidney disease (DKD) but less is known about the mechanisms of mesangial expansion, nodule formation, and its relationship with neovascularization. Changes in communication between injured cells serve as both a marker of disease progression and a mediator, promoting injury responses through positive feedback in surrounding cells. In this study, we aim to spatially localize changes in intra-glomerular communication between mesangial, endothelial, and epithelial cells. Methods: We subsetted the KPMP / HuBMAP snRNAseq atlas into reference (N=11) and diabetic (N=7) samples. Using the CellChat database, we modelled cell-cell communication in glomerular cell types. The snRNAseq atlas was used as reference to deconvolute 23 kidney spatial transcriptomics samples, including reference (N=6) and diabetic (N=10). The modelled cell-cell communication and associated pathway vectors were then localized onto glomeruli with COMMOT. Results: The cellular communication decreases in diabetic glomeruli (442) when compared to reference (1092). The overall loss of receptor-ligand interaction is more pronounced in diabetic mesangial cells, from 309 to 55 (p value < 10-9, Fisher's Exact). Some of the communication absent in diabetic mesangial cells include the JAG1 - NOTCH interaction with glomerular capillaries and podocytes and the Gas6 - TAM, cell proliferation, angiogenesis and immune activation. Associated pathways were differentially represented in healthy control and DKD spatial transcriptomic samples. Conclusions: These studies indicate a change in the intercellular communication in diabetic glomeruli. Identified pathways are potentially implicated in the process of neovascularization, mesangial expansion and glomerulosclerosis. Funding: NIDDK Support, Other NIH Support - HuBMAP

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