Multi scalar data integration reveals the immunopathological mechanisms associated with IgA nephropathy progression

IgA nephropathy (IgAN), the most common primary mesangial proliferative glomerulonephritis (MsPGN), represents the main cause of renal failure, while the precise pathogenetic mechanisms have not been fully determined. In this study, we employed multi-module data integration and functional experiment to explore the pathogenic programs underlying IgAN progression. Protein profiling of 21 IgAN samples showing progression and 28 samples without progression revealed that protein CXCL12, complement C3, and macrophage markers MRC1, and CD163 were negatively correlated with estimated glomerular filtration rate (eGFR) value, and poor prognosis (30% eGFR decline). Analysis of the single-cell RNA-sequencing (scRNA-seq) revealed that IgAN macrophages expressed high levels of CXCR4, PDGFB, TREM2, TNF, and complement C3, while Monocle pseudotime analysis suggested that these cells derived from the differentiation of infiltrating blood monocytes. Cross-species intercellular crosstalk analysis in human IgAN and ddY-mice IgAN model revealed that mesangial cells (MCs) in IgAN expressed high levels of CXCL12, CSF1 and PDGFRB and interacted with macrophages via the CXCL12-CXCR4, PDGFB-PDGFRB, and ITGAX/ITGAM-C3 axes. Interestingly, analysis of anti-Thy1.1 MsPGN scRNA-seq atlas revealed an inflammatory MCs (iMCs) phenotype which expressed Pdgfrb, Cxcl12, Csf1, and Il34 was associated with MsPGN injury process. Functional experiments revealed that specific blockade of the Cxcl12-Cxcr4 pathway significantly attenuated inflammatory injury, fibrosis, and decline of renal function in the MsPGN model. This study provides new insights into IgAN progression and may aid in the refinement of IgAN diagnosis and the optimization of treatment strategies.