دورية أكاديمية
Multi-omics and imaging mass cytometry characterization of human kidneys to identify pathways and phenotypes associated with impaired kidney function.
| العنوان: | Multi-omics and imaging mass cytometry characterization of human kidneys to identify pathways and phenotypes associated with impaired kidney function. |
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| المؤلفون: | Asowata EO; Bioscience Renal, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom; Department of Surgery, University of Cambridge and NIHR Biomedical Research Centre, Cambridge, United Kingdom., Romoli S; Bioscience Renal, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom., Sargeant R; Imaging and Data Analytics, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Cambridge, United Kingdom., Tan JY; Imaging and Data Analytics, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Cambridge, United Kingdom., Hoffmann S; Imaging and Data Analytics, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Cambridge, United Kingdom., Huang MM; Department of Surgery, University of Cambridge and NIHR Biomedical Research Centre, Cambridge, United Kingdom., Mahbubani KT; Department of Surgery, University of Cambridge and NIHR Biomedical Research Centre, Cambridge, United Kingdom., Krause FN; Bioscience Renal, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom; Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom., Jachimowicz D; Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden., Agren R; Translational Science and Experimental Medicine, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Koulman A; NIHR BRC Core Metabolomics and Lipidomics Laboratory, University of Cambridge, Cambridge, United Kingdom., Jenkins B; NIHR BRC Core Metabolomics and Lipidomics Laboratory, University of Cambridge, Cambridge, United Kingdom., Musial B; Bioscience Renal, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom., Griffin JL; Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom., Soderberg M; Department of Pathology, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Gothenburg, Sweden., Ling S; Imaging and Data Analytics, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Cambridge, United Kingdom., Hansen PBL; Bioscience Renal, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Saeb-Parsy K; Department of Surgery, University of Cambridge and NIHR Biomedical Research Centre, Cambridge, United Kingdom. Electronic address: ks10014@cam.ac.uk., Woollard KJ; Bioscience Renal, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom. Electronic address: kevin.woollard@astrazeneca.com. |
| المصدر: | Kidney international [Kidney Int] 2024 Jul; Vol. 106 (1), pp. 85-97. Date of Electronic Publication: 2024 Feb 29. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Country of Publication: United States NLM ID: 0323470 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1523-1755 (Electronic) Linking ISSN: 00852538 NLM ISO Abbreviation: Kidney Int Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2016- : New York : Elsevier Original Publication: New York, Springer-Verlag. |
| مواضيع طبية MeSH: | Phenotype* , Acute Kidney Injury*/metabolism , Acute Kidney Injury*/pathology , Acute Kidney Injury*/etiology, Humans ; Male ; Middle Aged ; Metabolomics/methods ; Female ; Kidney Transplantation/adverse effects ; Adult ; Image Cytometry/methods ; Kidney/pathology ; Kidney/metabolism ; Phospholipases A2/metabolism ; Arachidonic Acid/metabolism ; Kidney Tubules, Proximal/metabolism ; Kidney Tubules, Proximal/pathology ; Transcriptome ; Dinoprostone/metabolism ; Dinoprostone/analysis ; Fibroblasts/metabolism ; Gene Expression Profiling ; Epithelial Cells/metabolism ; Epithelial Cells/pathology ; Biopsy ; Multiomics |
| مستخلص: | Despite the recent advances in our understanding of the role of lipids, metabolites, and related enzymes in mediating kidney injury, there is limited integrated multi-omics data identifying potential metabolic pathways driving impaired kidney function. The limited availability of kidney biopsies from living donors with acute kidney injury has remained a major constraint. Here, we validated the use of deceased transplant donor kidneys as a good model to study acute kidney injury in humans and characterized these kidneys using imaging and multi-omics approaches. We noted consistent changes in kidney injury and inflammatory markers in donors with reduced kidney function. Neighborhood and correlation analyses of imaging mass cytometry data showed that subsets of kidney cells (proximal tubular cells and fibroblasts) are associated with the expression profile of kidney immune cells, potentially linking these cells to kidney inflammation. Integrated transcriptomic and metabolomic analysis of human kidneys showed that kidney arachidonic acid metabolism and seven other metabolic pathways were upregulated following diminished kidney function. To validate the arachidonic acid pathway in impaired kidney function we demonstrated increased levels of cytosolic phospholipase A2 protein and related lipid mediators (prostaglandin E2) in the injured kidneys. Further, inhibition of cytosolic phospholipase A2 reduced injury and inflammation in human kidney proximal tubular epithelial cells in vitro. Thus, our study identified cell types and metabolic pathways that may be critical for controlling inflammation associated with impaired kidney function in humans. (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.) |
| فهرسة مساهمة: | Keywords: arachidonic acid; imaging mass cytometry; kidney damage; kidney inflammation; lipidomics; metabolic pathways |
| المشرفين على المادة: | EC 3.1.1.4 (Phospholipases A2) 27YG812J1I (Arachidonic Acid) K7Q1JQR04M (Dinoprostone) |
| تواريخ الأحداث: | Date Created: 20240302 Date Completed: 20240621 Latest Revision: 20240729 |
| رمز التحديث: | 20240730 |
| DOI: | 10.1016/j.kint.2024.01.041 |
| PMID: | 38431215 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1523-1755 |
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| DOI: | 10.1016/j.kint.2024.01.041 |