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제목	Spatial and Single-Cell Analysis of Youth-Onset Type 2 Diabetes Reveals Diabetic Kidney Disease as a Myeloid and T-Cell Activation Disorder With Senescence
저자	Ye Ji Choi
출판정보	2025; 2025(1):
키워드	Diabetic Kidney Disease, Youth-Onset Type 2 Diabetes, Single-Cell RNA Sequencing, Spatial Transcriptomics, Senescence
초록	Youth-onset type 2 diabetes (Y-T2D) is associated with an accelerated course of diabetic kidney disease (DKD) compared to adult-onset T2D, yet the molecular drivers of early DKD remain poorly defined. Metabolic bariatric surgery (MBS) offers therapeutic benefit in Y-T2D, but its impact on DKD pathophysiology is unclear. We aimed to evaluate immune, fibrotic, and senescent changes in DKD and the effects of MBS using single-cell and spatial transcriptomics. Research kidney biopsies were collected before and 12 months post-MBS from adolescents with Y-T2D from the IMPROVE study. Lean controls (LC) were recruited from a cross-sectional study called CROCODILE. Kidney biopsies from LC (n=10), Y-T2D at baseline (n=8), and 12-months post-MBS (n=5) were analyzed using scRNA-seq and Visium spatial transcriptomics. scRNA-seq libraries were prepared using the 10X Genomics platform, and Visium was performed for spatial profiling. Data were preprocessed with Seurat and pseudobulk differential expression was performed using DESeq2. Cell-type deconvolution, spatial gene-set scoring and cell-cell interaction analysis characterized kidney microarchitecture. At baseline, Y-T2D exhibited significant immune activation (e.g., HLA class I/II upregulation) and cell senescence, with myeloid infiltration and T-cell activation compared to LC. Fibroblast interactions were prominent, indicating a pro-inflammatory, pro-fibrotic environment. Post-MBS, T-cell activation was reduced but senescence and myeloid infiltration persisted with no significant changes in key cell types (e.g., PT-S1/S2, fibroblasts; p > 0.2). DKD in Y-T2D is characterized by myeloid and T-cell activation, cellular senescence, and fibrosis. While MBS attenuates systemic inflammation, targeted immunomodulatory or senotherapeutic interventions may be necessary to fully mitigate DKD progression. Future studies should investigate pharmacologic approaches that target myeloid-T cell interactions and senescence pathways to improve renal outcomes in Y-T2D.
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