Spatial-resolved metabolomics reveals tissue-specific metabolic reprogramming in diabetic nephropathy by using mass spectrometry imaging

Zhonghua Wang; Wenqing Fu; Meiling Huo; Bingshu He; Yaqi Liu; Lu Tian; Wanfang Li; Zhi Zhou; Baili Wang; Jianzhen Xia; Yanhua Chen; Jinfeng Wei; Zeper Abliz

doi:10.1016/j.apsb.2021.05.013

Spatial-resolved metabolomics reveals tissue-specific metabolic reprogramming in diabetic nephropathy by using mass spectrometry imaging

Acta Pharm Sin B. 2021 Nov;11(11):3665-3677. doi: 10.1016/j.apsb.2021.05.013. Epub 2021 May 20.

Authors

Zhonghua Wang^{1

2

3}, Wenqing Fu^{1

2}, Meiling Huo^{1

2}, Bingshu He², Yaqi Liu², Lu Tian⁴, Wanfang Li⁴, Zhi Zhou^{1

2}, Baili Wang⁵, Jianzhen Xia⁵, Yanhua Chen^{1

2}, Jinfeng Wei⁴, Zeper Abliz^{1

2

3}

Affiliations

¹ Key Laboratory of Mass Spectrometry Imaging and Metabolomics (Minzu University of China), National Ethnic Affairs Commission, Beijing 100081, China.
² College of Life and Environmental Sciences, Minzu University of China, Beijing 100081, China.
³ Key Laboratory of Ethnomedicine of Ministry of Education, School of Pharmacy, Minzu University of China, Beijing 100081, China.
⁴ New Drug Safety Evaluation Center, Institute of Materia Medica, Peking Union Medical College, Beijing 100050, China.
⁵ School Hospital, Minzu University of China, Beijing 100081, China.

Abstract

Detailed knowledge on tissue-specific metabolic reprogramming in diabetic nephropathy (DN) is vital for more accurate understanding the molecular pathological signature and developing novel therapeutic strategies. In the present study, a spatial-resolved metabolomics approach based on air flow-assisted desorption electrospray ionization (AFADESI) and matrix-assisted laser desorption ionization (MALDI) integrated mass spectrometry imaging (MSI) was proposed to investigate tissue-specific metabolic alterations in the kidneys of high-fat diet-fed and streptozotocin (STZ)-treated DN rats and the therapeutic effect of astragaloside IV, a potential anti-diabetic drug, against DN. As a result, a wide range of functional metabolites including sugars, amino acids, nucleotides and their derivatives, fatty acids, phospholipids, sphingolipids, glycerides, carnitine and its derivatives, vitamins, peptides, and metal ions associated with DN were identified and their unique distribution patterns in the rat kidney were visualized with high chemical specificity and high spatial resolution. These region-specific metabolic disturbances were ameliorated by repeated oral administration of astragaloside IV (100 mg/kg) for 12 weeks. This study provided more comprehensive and detailed information about the tissue-specific metabolic reprogramming and molecular pathological signature in the kidney of diabetic rats. These findings highlighted the promising potential of AFADESI and MALDI integrated MSI based metabolomics approach for application in metabolic kidney diseases.

Keywords: ADP, adenosine diphosphate; AFADESI, air flow-assisted desorption electrospray ionization; AGEs, advanced glycation end products; AMP, adenosine monophosphate; AMPK, adenosine monophosphate activated protein kinase; AST, astragaloside IV; ATP, adenosine triphosphate; Astragaloside IV; BUN, blood urea nitrogen; CL, cardiolipin; Cre, creatinine; DAG, diacylglycerol; DESI, desorption electrospray ionization; DM, diabetes mellitus; DN, diabetic nephropathy; DPA, docosapentaenoic acid; Diabetic nephropathy; ESKD, end-stage kidney disease; FBG, fasting blood glucose; GLU, glucose; GMP, guanosine monophosphate; GSH, glutathione; H&E, hematoxylin and eosin; HPLC, high-performance liquid chromatography; HbA1c, glycosylated hemoglobin; LysoPC, lysophosphatidylcholine; LysoPG, lysophosphatidylglycerol; MALDI, matrix-assisted laser desorption ionization; MS, mass spectrometry; MSI, mass spectrometry imaging; Mass spectrometry imaging; Metabolic reprogramming; NMR, nuclear magnetic resonance; Na-CMC, sodium carboxymethyl cellulose; PA, phosphatidic acid; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PG, phosphatidylglycerol; PPP, pentose phosphate pathway; PS, phosphatidylserine; PUFA, polyunsaturated fatty acids; ROI, regions of interest; ROS, reactive oxygen species; SDH, succinate dehydrogenase; SGLTs, sodium-glucose cotransporters; SM, sphingomyelin; STZ, streptozotocin; Spatial-resolved metabolomics; TCA, tricarboxylic acid; TCHO, total cholesterol; TG, triglyceride; UMP, uridine monophosphate; VIP, variable importance in projection; p-AMPK, phosphorylated adenosine monophosphate activated protein kinase.