BACKGROUND: The precise mechanisms responsible for renal injury in IgA nephropathy (IgAN) are not fully understood. Our study employed an extensive scRNA-seq analysis of kidney biopsies obtained from individuals with IgAN, with a specific emphasis on investigating the involvement of renal endothelial cells. METHODS: We obtained data from the Gene Expression Omnibus database and conducted bioinformatics analysis, which included enrichment analysis of differentially expressed genes, AUCell analysis, and high-dimensional weighted gene co-expression network analysis (hdWGCNA). The results of these analyses were further validated using human renal glomerular endothelial cells (HRGECs). RESULTS: The ScRNA-seq data uncovered notable variations in gene expression between IgAN and control kidney tissues. The enrichment analysis using AUCell demonstrated a high presence of adhesion molecules and components related to the mitogen-activated protein kinase signaling pathway within the renal endothelial cells. Furthermore, through hdWGCNA analysis, it was discovered that interleukin (IL)-6, Rac1, and cadherin exhibited associations with the renal endothelial cells. Stimulation of HRGECs with IL-6/IL-6 receptor resulted in a significant reduction in VE-cad expression while inhibiting Rac1 led to a substantial decrease in Rac1-GTP levels and an increase in VE-cad expression. CONCLUSION: This study presents novel findings regarding the contribution of renal endothelial cells to the development of IgAN, as it demonstrates that IL-6 negatively regulates VE-cad expression in HRGECs via Rac1. These results highlight the significant involvement of renal endothelial cells in the pathogenesis of IgAN.