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Glomerular spatial transcriptomics of IgA nephropathy according to the presence of mesangial proliferation

Background Mesangial proliferation is a key pathologic feature of diagnosis and also a risk factor for progression in immunoglobulin A nephropathy (IgAN). We aimed to investigate the gene expression profiles of IgAN glomerulus according to the presence of mesangial proliferation. Methods We performed spatial-specific transcriptomic profiling for formalin-fixed-paraffin-embedded kidney biopsy tissues using the GeoMX Digital Spatial Profiler. A total of 3 glomeruli with direct pathologic classification for each case were profiled, including 12 cases (4 M1-IgAN, 4 M0-IgAN, and 4 donor controls). The differentially expressed genes (DEGs) were analyzed between the groups with gene ontology (GO) term annotation. Results In the result which successfully enriched glom-specific genes, M1-IgAN were distinctively separated from controls (77 upregulated and 55 downregulated DEGs), while certain DEGs were identified between M1-IgAN and M0-IgAN cases (24 upregulated and 8 downregulated DEGs) or between M0 and controls (1 upregulated and 16 downregulated DEGs). The upregulated DEG that was consistent in M1-IgAN and M0-IgAN cases was TCF21 which is known as early podocyte injury marker while the DEGs uniformly downregulated in IgAN cases included ATF3, EGR1, DUSP1, FOS, JUNB, KLF2, KLF4, NR4A1, RHOB, and ZFP36. Glomeruli from M1-IgAN cases were significantly enriched for cell surface/adhesion molecules and the gene expressions that consist vascular development or extracellular matrix. Conclusion We found certain transcriptomic differences according to the histologic changes in IgAN which was present even in the early stage of the disease. Spatial transcriptomic analysis may contribute to dissecting structure-specific pathogenesis and molecular changes in IgAN.