The international journal of biochemistry & cell biology · 2026
Single-cell transcriptomic analysis unveils dysregulated macrophage-podocyte crosstalk in membranous nephropathy.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Zhang Yinghui, Huang Siyue, Li Xueting, Xu Chengyun, Ke Ben
Аннотация
BACKGROUND: Membranous nephropathy (MN) is an antibody-mediated glomerular disease, but the cellular networks driving injury remain poorly defined.
METHODS: We integrated the cationic bovine serum albumin (cBSA)-induced mouse MN model with single-cell RNA sequencing (scRNA-seq) to profile renal cells. Bioinformatic analyses included clustering, differential expression, pathway enrichment, and cell-cell communication inference (CellChat).
RESULTS: We successfully established a cBSA-induced MN mouse model exhibiting characteristic pathological features, including glomerular basement membrane thickening and IgG deposition. Single-cell transcriptomics revealed a profoundly remodeled renal cellular landscape in MN, characterized by immune activation (increases in macrophages, B cells, T cells, and NK cells) and concomitant tubular injury (significant loss of proximal tubule cells). We identified an imbalanced adaptive immune response: T follicular helper (Tfh) cells expanded, but plasma cells decreased, suggesting disrupted differentiation. Pathway analysis indicated metabolic reprogramming in B cells, ER stress in plasma cells, and pro-inflammatory activation in macrophages. Crucially, cell-cell communication analysis uncovered a rewired pathogenic macrophage-podocyte axis. This axis was defined by a dual imbalance: a gain-of-function in injury-promoting signals (Spp1-integrin) coupled with a loss-of-function in homeostatic signals (collagen IV).
CONCLUSION: This study provides a comprehensive cellular atlas of MN and delineates a dysregulated macrophage-podocyte crosstalk as a key driver of glomerular injury, highlighting this axis as a promising target for therapeutic intervention.
METHODS: We integrated the cationic bovine serum albumin (cBSA)-induced mouse MN model with single-cell RNA sequencing (scRNA-seq) to profile renal cells. Bioinformatic analyses included clustering, differential expression, pathway enrichment, and cell-cell communication inference (CellChat).
RESULTS: We successfully established a cBSA-induced MN mouse model exhibiting characteristic pathological features, including glomerular basement membrane thickening and IgG deposition. Single-cell transcriptomics revealed a profoundly remodeled renal cellular landscape in MN, characterized by immune activation (increases in macrophages, B cells, T cells, and NK cells) and concomitant tubular injury (significant loss of proximal tubule cells). We identified an imbalanced adaptive immune response: T follicular helper (Tfh) cells expanded, but plasma cells decreased, suggesting disrupted differentiation. Pathway analysis indicated metabolic reprogramming in B cells, ER stress in plasma cells, and pro-inflammatory activation in macrophages. Crucially, cell-cell communication analysis uncovered a rewired pathogenic macrophage-podocyte axis. This axis was defined by a dual imbalance: a gain-of-function in injury-promoting signals (Spp1-integrin) coupled with a loss-of-function in homeostatic signals (collagen IV).
CONCLUSION: This study provides a comprehensive cellular atlas of MN and delineates a dysregulated macrophage-podocyte crosstalk as a key driver of glomerular injury, highlighting this axis as a promising target for therapeutic intervention.