Original articles
Zhonghua Wang, Bingshu He, Yaqi Liu, Meiling Huo, Wenqing Fu, Chunyan Yang, Jinfeng Wei, Zeper Abliz. In situ metabolomics in nephrotoxicity of aristolochic acids based on air flow-assisted desorption electrospray ionization mass spectrometry imaging[J]. Acta Pharmaceutica Sinica B, 2020, 10(6): 1083-1093

In situ metabolomics in nephrotoxicity of aristolochic acids based on air flow-assisted desorption electrospray ionization mass spectrometry imaging
Zhonghua Wanga,c, Bingshu Hea, Yaqi Liua, Meiling Huoa, Wenqing Fua, Chunyan Yangb, Jinfeng Weib, Zeper Abliza,c,d
a Center for Imaging and Systems Biology, College of Life and Environmental Sciences, Minzu University of China, Beijing 100081, China;
b New Drug Safety Evaluation Center, Institute of Materia Medica, Peking Union Medical College, Beijing 100050, China;
c Key Laboratory of Ethnomedicine of Ministry of Education, Minzu University of China, Beijing 100081, China;
d School of Pharmacy, Minzu University of China, Beijing 100081, China
Abstract:
Understanding of the nephrotoxicity induced by drug candidates is vital to drug discovery and development. Herein, an in situ metabolomics method based on air flow-assisted desorption electrospray ionization mass spectrometry imaging (AFADESI-MSI) was established for direct analysis of metabolites in renal tissue sections. This method was subsequently applied to investigate spatially resolved metabolic profile changes in rat kidney after the administration of aristolochic acid I, a known nephrotoxic drug, aimed to discover metabolites associated with nephrotoxicity. As a result, 38 metabolites related to the arginine-creatinine metabolic pathway, the urea cycle, the serine synthesis pathway, metabolism of lipids, choline, histamine, lysine, and adenosine triphosphate were significantly changed in the group treated with aristolochic acid I. These metabolites exhibited a unique distribution in rat kidney and a good spatial match with histopathological renal lesions. This study provides new insights into the mechanisms underlying aristolochic acids nephrotoxicity and demonstrates that AFADESI-MSI-based in situ metabolomics is a promising technique for investigation of the molecular mechanism of drug toxicity.
Key words:    Aristolochic acid    Nephrotoxicity    Mass spectrometry imaging    In situ metabolomics    AFADESI   
Received: 2019-07-01     Revised: 2019-11-11
DOI: 10.1016/j.apsb.2019.12.004
Funds: This research was supported by the National Key Research and Development Program of China (No. 2017YFC1704000) and Outstanding Talent Support Program of Beijing, China (No. 2017000020124G272).
Corresponding author: Zeper Abliz     Email:zeper@muc.edu.cn
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Zhonghua Wang
Bingshu He
Yaqi Liu
Meiling Huo
Wenqing Fu
Chunyan Yang
Jinfeng Wei
Zeper Abliz

References:
1. Chan W, Cui L, Xu G, Cai Z. Study of the phase I and phase II metabolism of nephrotoxin aristolochic acid by liquid chromatography/tandem mass spectrometry. Rapid Commun Mass Spectrom 2006; 20:1755-60.
2. Mengs U, Lang W, Poch JA. The carcinogenic action of aristolochic acid in rats. Arch Toxicol 1982;51:107-19.
3. Vanherweghem JL, Tielemans C, Abramowicz D, Depierreux M, Vanhaelen-Fastre R, Vanhaelen M, et al. Rapidly progressive interstitial renal fibrosis in young women:association with slimming regimen including Chinese herbs. Lancet 1993;341:387-91.
4. Liu MC, Maruyama S, Mizuno M, Morita Y, Hanaki S, Yuzawa Y, et al. The nephrotoxicity of Aristolochia manshuriensis in rats is attributable to its aristolochic acids. J Clin Exp Nephrol 2003;7:186-94.
5. Lord GM, Tagore R, Cook T, Gower P, Pusey CD. Nephropathy caused by Chinese herbs in the UK. Lancet 1999;354:481-2.
6. Gökmen MR, Cosyns JP, Arlt VM, Stiborová M, Phillips DH, Schmeiser HH, et al. The epidemiology, diagnosis, and management of aristolochic acid nephropathy:a narrative review. Ann Intern Med 2013;158:469-77.
7. Xu X, Nie S, Liu Z, Chen C, Xu G, Zha Y, et al. Epidemiology and clinical correlates of AKI in Chinese hospitalized adults. Clin J Am Soc Nephrol 2015;10:1510.
8. Grollman AP, Shibutani S, Moriya M, Miller F, Wu L, Moll U, et al. Aristolochic acid and the etiology of endemic (Balkan) nephropathy. Proc Natl Acad Sci USA 2007;104:12129.
9. Debelle FD, Vanherweghem JL, Nortier JL. Aristolochic acid nephropathy:a worldwide problem. Kidney Int 2008;74:158-69.
10. Debelle FD, Nortier JL, de Prez EG, Garbar CH, Vienne AR, Salmon IJ, et al. Aristolochic acids induce chronic renal failure with interstitial fibrosis in salt-depleted rats. J Am Soc Nephrol 2002;13:431.
11. Shibutani S, Dong H, Suzuki N, Ueda S, Miller F, Grollman AP. Selective toxicity of aristolochic acids I and II. Drug Metab Dispos 2007; 35:1217.
12. Yang L, Li X, Wang H. Possible mechanisms explaining the tendency towards interstitial fibrosis in aristolochic acid-induced acute tubular necrosis. Nephrol Dial Transplant 2006;22:445-56.
13. Randerath K, Reddy MV, Gupta RC. 32P-labeling test for DNA damage. Proc Natl Acad Sci USA 1981;78:6126.
14. Prabu SM, Muthumani M. Silibinin ameliorates arsenic induced nephrotoxicity by abrogation of oxidative stress, inflammation and apoptosis in rats. Mol Biol Rep 2012;39:11201-16.
15. Pozdzik AA, Salmon IJ, Husson CP, Decaestecker C, Rogier E, Bourgeade MF, et al. Patterns of interstitial inflammation during the evolution of renal injury in experimental aristolochic acid nephropathy. Nephrol Dial Transplant 2008;23:2480-91.
16. Hsin YH, Cheng CH, Tzen JT, Wu MJ, Shu KH, Chen HC. Effect of aristolochic acid on intracellular calcium concentration and its links with apoptosis in renal tubular cells. Apoptosis 2006;11:2167.
17. Zhu S, Wang Y, Jin J, Guan C, Li M, Xi C, et al. Endoplasmic reticulum stress mediates aristolochic acid I-induced apoptosis in human renal proximal tubular epithelial cells. Toxicol In Vitro 2012;26:663-71.
18. Pan L, Han P, Ma S, Peng R, Wang C, Kong W, et al. Abnormal metabolism of gut microbiota reveals the possible molecular mechanism of nephropathy induced by hyperuricemia. Acta Pharm Sin B 2020;10:249-61.
19. Shi J, Cao B, Wang XW, Aa JY, Duan JA, Zhu XX, et al. Metabolomics and its application to the evaluation of the efficacy and toxicity of traditional Chinese herb medicines. J Chromatogr B 2016; 1026:204-16.
20. Ni Y, Su M, Qiu Y, Chen M, Liu Y, Zhao A, et al. Metabolic profiling using combined GCeMS and LCeMS provides a systems understanding of aristolochic acid-induced nephrotoxicity in rat. FEBS Lett 2007;581:707-11.
21. Zhao YY, Wang HL, Cheng XL, Wei F, Bai X, Lin RC, et al. Metabolomics analysis reveals the association between lipid abnormalities and oxidative stress, inflammation, fibrosis, and Nrf2 dysfunction in aristolochic acid-induced nephropathy. Sci Rep 2015;5:12936.
22. Zhao YY, Tang DD, Chen H, Mao JR, Bai X, Cheng XH, et al. Urinary metabolomics and biomarkers of aristolochic acid nephrotoxicity by UPLCeQTOF/HDMS. Bioanalysis 2015;7:685-700.
23. Lin S, Chan W, Li J, Cai Z. Liquid chromatography/mass spectrometry for investigating the biochemical effects induced by aristolochic acid in rats:the plasma metabolome. Rapid Commun Mass Spectrom 2010; 24:1312-8.
24. Chen M, Su M, Zhao L, Jiang J, Liu P, Cheng J, et al. Metabolomic study of aristolochic acid-induced nephrotoxicity in rats. J Proteome Res 2006;5:995-1002.
25. Moreno-Gordaliza E, Esteban-Fernández D, Lázaro A, Humanes B, Aboulmagd S, Tejedor A, et al. MALDI-LTQ-Orbitrap mass spectrometry imaging for lipidomic analysis in kidney under cisplatin chemotherapy. Talanta 2017;164:16-26.
26. Römpp A, Spengler B. Mass spectrometry imaging with high resolution in mass and space. Histochem Cell Biol 2013;139:759-83.
27. Greer T, Sturm R, Li L. Mass spectrometry imaging for drugs and metabolites. J Proteomics 2011;74:2617-31.
28. Cornett DS, Reyzer ML, Chaurand P, Caprioli RM. MALDI imaging mass spectrometry:molecular snapshots of biochemical systems. Nat Methods 2007;4:828.
29. Takáts Z, Wiseman JM, Gologan B, Cooks RG. Mass spectrometry sampling under ambient conditions with desorption electrospray ionization. Science 2004;306:471.
30. Liu H, Li W, He Q, Xue J, Wang J, Xiong C, et al. Mass spectrometry imaging of kidney tissue sections of rat subjected to unilateral ureteral obstruction. Sci Rep 2017;7:41954.
31. Altelaar AFM, Klinkert I, Jalink K, de Lange RPJ, Adan RAH, Heeren RMA, et al. Gold-enhanced biomolecular surface imaging of cells and tissue by SIMS and MALDI mass spectrometry. Anal Chem 2006;78:734-42.
32. He J, Sun C, Li T, Luo Z, Huang L, Song X, et al. A sensitive and wide coverage ambient mass spectrometry imaging method for functional metabolites based molecular histology. Adv Sci 2018;5. 1800250.
33. Sun C, Li T, Song X, Huang L, Zang Q, Xu J, et al. Spatially resolved metabolomics to discover tumor-associated metabolic alterations. Proc Natl Acad Sci USA 2019;116:52.
34. Li T, He J, Mao X, Bi Y, Luo Z, Guo C, et al. In situ biomarker discovery and label-free molecular histopathological diagnosis of lung cancer by ambient mass spectrometry imaging. Sci Rep 2015;5:14089.
35. He J, Luo Z, Huang L, He J, Chen Y, Rong X, et al. Ambient mass spectrometry imaging metabolomics method provides novel insights into the action mechanism of drug candidates. Anal Chem 2015;87:5372-9.
36. Vaidya VS, Ozer JS, Dieterle F, Collings FB, Ramirez V, Troth S, et al. Kidney injury molecule-1 outperforms traditional biomarkers of kidney injury in preclinical biomarker qualification studies. Nat Biotechnol 2010;28:478-85.
37. Bonventre JV, Vaidya VS, Schmouder R, Feig P, Dieterle F. Nextgeneration biomarkers for detecting kidney toxicity. Nat Biotechnol 2010;28:436-40.
38. Tong BC, Barbul A. Cellular and physiological effects of arginine. Mini Rev Med Chem 2004;4:823-32.
39. Benito S, Sánchez A, Unceta N, Andrade F, Aldámiz-Echevarria L, Goicolea MA, et al. LCeQTOF-MS-based targeted metabolomics of arginineecreatine metabolic pathway-related compounds in plasma:application to identify potential biomarkers in pediatric chronic kidney disease. Anal Bioanal Chem 2016;408:747-60.
40. Benito S, Sánchez-Ortega A, Unceta N, Jansen JJ, Postma G, Andrade F, et al. Plasma biomarker discovery for early chronic kidney disease diagnosis based on chemometric approaches using LCeQTOF targeted metabolomics data. J Pharm Biomed Anal 2018;149:46-56.
41. Wang ZH, He BS, Sun CL, Song XW, He JM, Zhang RP, et al. Study on tissue distribution of a variety of endogenous metabolites by air flow assisted ionization-ultra high resolution mass spectrometry imaging. Chin J Anal Chem 2018;46:406-11.
42. Lou Y, Li J, Lu Y, Wang X, Jiao R, Wang S, et al. Aristolochic acidinduced destruction of organic ion transporters and fatty acid metabolic disorder in the kidney of rats. Toxicol Lett 2011;201:72-9.
43. Galvan DL, Green NH, Danesh FR. The hallmarks of mitochondrial dysfunction in chronic kidney disease. Kidney Int 2017;92:1051-7.
44. Wenk MR. The emerging field of lipidomics. Nat Rev Drug Discov 2005;4:594-610.
45. di Paolo G, de Camilli P. Phosphoinositides in cell regulation and membrane dynamics. Nature 2006;443:651-7.
46. Xu Y, Guo N, Dou D, Ran X, Liu C. Metabolomics analysis of anaphylactoid reaction reveals its mechanism in a rat model. Asian Pac J Allergy Immunol 2017;35:224-32.
47. Che RC, Yuan YG, Huang SM, Zhang AH. Mitochondrial dysfunction in the pathophysiology of renal diseases. Am J Physiol Renal Physiol 2014;306:367-78.
48. Qi X, Cai Y, Gong L, Liu L, Chen F, Xiao Y, et al. Role of mitochondrial permeability transition in human renal tubular epithelial cell death induced by aristolochic acid. Toxicol Appl Pharmacol 2007;222:105-10.
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