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

BackgroundMesangial 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.MethodsWe 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.ResultsIn 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.ConclusionWe 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.Significance StatementImmunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis with distinct pathologic features of mesangial proliferation with IgA deposition. The authors used spatial transcriptomic analysis to investigate the gene expression profiles from glomeruli with direct pathology annotation. The analysis revealed notable differentially expressed genes in IgAN with and without mesangial proliferation including early podocyte changes, expressions of cell adhesion molecules, alteration in transcription factor pathway, vascular development and extracellular matrix production. The current spatial transcriptomic analysis suggests notable gene expression profiles that may contribute to pathogenesis and progression of IgAN.