Journal Article Epublish
PubMed: 42058134 DOI: 10.1093/lifemeta/loaf019
Spatially segregated multiomics decodes metformin-mediated function-specific metabolic characteristics in diabetic kidney disease.
Life Metab 4(5):loaf019
Authors: 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
Affiliations
- International Advanced Functional Omics Platform, Scientific Experiment Center, Public Research Center, Hainan Medical University, Haikou, Hainan 571199, China.
- International Advanced Functional Omics Platform, Scientific Experiment Center, Public Research Center, Hainan Medical University, Haikou, Hainan 571199, China. Graduate School, Second Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150040, China.
- Graduate School, Second Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150040, China.
- First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang 150040, China.
Abstract
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 and function-specific therapeutic pathways related to the anatomical multiregion of diabetic mouse kidneys.
MeSH
Kidney Diseases, Ether, Coenzyme A, Kidney Medulla, Diabetic Nephropathies, Multiple Chronic Conditions, Kidney, Metabolomics, Proteomics, Therapeutics, Metformin