Single nucleus RNA-seq reveals the process from onset to chronic kidney disease in IgA nephropathy

IgA nephropathy (IgAN) is a common form of glomerulonephritis. According to the established multi-hit theory of IgAN pathogenesis, the final hit is the mesangial deposition of IgA1-containing immune complexes, leading to characteristic pathological features such as mesangial cell proliferation and expansion of extracellular matrix. We analyzed several public transcriptomic datasets, including microarray and bulk RNA-sequencing, to identify pathway alterations in IgAN patients and progressors. We also generated our own single-nucleus RNA-sequencing dataset from IgAN kidney biopsies with normal or reduced estimated glomerular filtration rate and integrated it with a publicly available healthy control dataset to comprehensively examine cell type-specific changes during IgAN progression. Pathways related to complement activation, focal adhesion, and collagen formation were significantly enhanced in IgAN compared to healthy controls. Our snRNA-seq data identified two mesenchymal stromal cell (MSC) clusters with higher scores in these pathways than other cell types, which were progressively perturbed as eGFR declined. We observed a potential transition from mesangial cells to myofibroblasts within MSCs, accompanied by increased expression of genes involved in complement activation, humoral immunity, collagen organization, and extracellular matrix assembly. This transition could be partially reversed through in silico knockdown of certain transcription factors, such as PRRX1.