Single-Nucleus Transcriptomic Atlas Reveals Disease-Associated Cellular States in Human Glomerular Diseases.

Introduction: Glomerular diseases are a major cause of chronic kidney disease and kidney failure worldwide, yet the cellular mechanisms underlying their heterogeneity remain incompletely understood. Single-nucleus RNA sequencing (snRNA-seq) enables high-resolution characterization of transcriptional alterations across diverse kidney cell populations. Methods: We performed snRNA-seq on snap-frozen kidney biopsy tissues obtained from treatment-naïve patients with minimal change disease (MCD), membranous nephropathy (MN), IgA nephropathy (IgAN), and diabetic kidney disease (DKD), together with control kidney samples. In total, 333,938 nuclei from 37 individuals were analyzed to define disease-associated transcriptional programs across kidney cell types. Results: Upregulated transcripts formed disease-specific programs that were shared across multiple cell types, whereas downregulated transcripts were largely cell type-specific and conserved across diseases. We identified disease-associated cellular states, including a glomerular epithelial population exhibiting a hybrid transcriptional profile shared between podocytes and parietal epithelial cells (PECs); a podocyte subpopulation with endocytosis-related gene expression, correlated with proteinuria severity and treatment response; and expansion of periostin (POSTN)-expressing myofibroblasts, inversely associated with estimated glomerular filtration rate (eGFR) and spatially colocalized with podocyte injury. Each cellular state was independently recovered in external single-cell cohorts. Conclusion: Single-nucleus transcriptomic profiling of human kidney biopsy tissues reveals disease-specific and shared cellular programs across major glomerular diseases. This resource provides insight into the cellular mechanisms underlying glomerular injury and identifies disease-associated cell states that may contribute to disease progression.