Single cell sequencing and spatial multiomics of diabetic kidney segmentation insights zonation-specific therapeutic metabolic pathways

作者：Shi Qiu, Zhibo Wang, Sifan Guo, Dandan Xie, Ying Cai, Xian Wang, Chunsheng Lin, Songqi Tang, Yiqiang Xie, Aihua Zhang · 发表于：Cell Insight · 年份：2025 · DOI：10.1016/j.cellin.2025.100252 · 被引用次数：20 · 研究领域：Single-cell and spatial transcriptomics、Cell Image Analysis Techniques、Metabolomics and Mass Spectrometry Studies

Diabetic nephropathy (DN) exhibits profound spatial metabolic heterogeneity across kidney regions, yet how compartmentalized pathways drive disease progression remains poorly defined. A deeper understanding of the organizational spatial environment and metabolic pathways of diabetic kidney damage will provide new insights to develop new therapies. By integrating high-resolution spatial multi-omics and single-cell transcriptomics, we mapped region-specific metabolic dysregulation in diabetic kidneys, identifying glutathione metabolism, pentose phosphate, and glycolytic pathways as zonally disrupted in cortical and medullary regions. Spatial metabolomics revealed distinct anatomical clustering of ten clinically associated metabolites, while spatial proteomic profiling uncovered sixty-four region-enriched proteins linked to these pathways. Specifically, depending on anatomic location, spatial protein signatures across multiple regions of diabetic mouse kidneys were enriched in each segmentation, respectively. Cross-species integration identified GPX3 as a fibroblast-enriched biomarker strongly correlated with kidney dysfunction and closely related to clinical indicators. Notably, astragaloside IV (ASIV) treatment reversed spatial metabolic perturbations in diabetic mice, restoring glutathione and glycolytic pathway activity in a compartment-specific manner. Single-cell analyses identified five cell types-endothelial cells, fibroblasts, epithelial cells, macrophages and neutrophi...