Qiu Shi, Wang Zhibo, Guo Sifan, Xie Dandan, Cai Ying, Wang Xian, Lin Chunsheng, Tang Songqi, Xie Yiqiang, Zhang Aihua
International Advanced Functional Omics Platform, Scientific Experiment Center, Hainan Engineering Research Center for Biological Sample Resources of Major Diseases, Hainan Medical University, Xueyuan Road 3, Haikou 571199, Hainan, China.
Graduate School, Second Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin 150040, Heilongjiang, China.
Cell Insight. 2025 May 13;4(3):100252. doi: 10.1016/j.cellin.2025.100252. eCollection 2025 Jun.
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 neutrophils-and further revealed fibroblasts as key contributors to regulatory effects via GPX3 overexpression. Importantly, the higher expression of Gpx3 in fibroblasts compared to other cell types, Gpx3 (AUC = 0.995), was further validated, demonstrating the high sensitivity and specificity for DN patients. This multimodal atlas establishes the spatially resolved metabolic blueprint of DN, bridging molecular zoning with anatomical localization of renal tissue to unveil actionable therapeutic targets for metabolic disorders in kidney disease.
糖尿病肾病（DN）在肾脏区域表现出深刻的空间代谢异质性，但分区化途径如何驱动疾病进展仍不清楚。深入了解糖尿病肾脏损伤的组织空间环境和代谢途径将为开发新疗法提供新见解。通过整合高分辨率空间多组学和单细胞转录组学，我们绘制了糖尿病肾脏中区域特异性的代谢失调图谱，确定谷胱甘肽代谢、磷酸戊糖和糖酵解途径在皮质和髓质区域存在区域性功能紊乱。空间代谢组学揭示了十种临床相关代谢物的独特解剖学聚类，而空间蛋白质组分析发现了与这些途径相关的64种区域富集蛋白。具体而言，根据解剖位置，糖尿病小鼠肾脏多个区域的空间蛋白质特征在每个节段中分别富集。跨物种整合确定GPX3是一种在成纤维细胞中富集的生物标志物，与肾功能障碍密切相关且与临床指标密切相关。值得注意的是，黄芪甲苷（ASIV）治疗逆转了糖尿病小鼠的空间代谢紊乱，以区域特异性方式恢复了谷胱甘肽和糖酵解途径的活性。单细胞分析确定了五种细胞类型——内皮细胞、成纤维细胞、上皮细胞、巨噬细胞和中性粒细胞——并进一步揭示成纤维细胞是通过GPX3过表达产生调节作用的关键因素。重要的是，与其他细胞类型相比，成纤维细胞中Gpx3的高表达（AUC = 0.995）得到了进一步验证，证明了对DN患者具有高敏感性和特异性。这个多模态图谱建立了DN的空间分辨代谢蓝图，将分子分区与肾组织的解剖定位联系起来，以揭示肾脏疾病代谢紊乱的可操作治疗靶点。
