Spatially segregated multiomics decodes metformin-mediated functional-specific metabolic characteristics in diabetic kidney disease

作者：Shi Qiu, Dandan Xie, Sifan Guo, Zhibo Wang, Xian Wang, Ying Cai, Chunsheng Lin, Hong Yao, Yu Guan, Qiqi Zhao, Qiang Yang, Yiqiang Xie, Songqi Tang, Aihua Zhang · 发表于：Life Metabolism · 年份：2025 · DOI：10.1093/lifemeta/loaf019 · 被引用次数：10 · 研究领域：Metabolomics and Mass Spectrometry Studies、Metabolism and Genetic Disorders、Folate and B Vitamins Research

Understanding the specific metabolic changes in multiple regions of the kidney is crucial to revealing the underlying mechanism and developing effective targets for diabetic nephropathy (DN). In this study, integrated spatially resolved metabolomics and proteomics combined with mass spectrometry imaging (MSI) revealed a multi-scale region profile of the diabetic kidney. Based on anatomic location, spatial metabolomics revealed eight region-specific metabolite biomarkers uniquely localized to kidney segments, which were closely correlated to the clinical parameters of patients with DN. Specifically, treatment with metformin (MET) enriched inosinic acid, adenosine 3',5'-diphosphate, nicotinamide adenine dinucleotide (NADH), and hydrated NADH (NADHX) levels in the cortex (Cor) and the outer stripe of kidney medulla (OM) anatomical subregions, while in the inner stripe of kidney medulla (IM) segmentation, the p-cresol sulfate level was downregulated. Comparing differently expressed proteins in each region showed that nephrosis 2 (Nphs2) was the highest loading feature. A further region-specific analysis of pathway enrichment characteristics indicated that the purine and ether lipid metabolism pathways were enriched in the Cor and OM regions, whereas the pantothenate and coenzyme A (CoA) biosynthesis pathways were mainly enriched in the IM region in response to MET treatment. Taken together, the spatially segregated metabolomics and proteomics studies reveal MET-mediated proteins ...