1. Multi-omics and imaging mass cytometry characterization of human kidneys to identify pathways and phenotypes associated with impaired kidney function.
- Author
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Asowata EO, Romoli S, Sargeant R, Tan JY, Hoffmann S, Huang MM, Mahbubani KT, Krause FN, Jachimowicz D, Agren R, Koulman A, Jenkins B, Musial B, Griffin JL, Soderberg M, Ling S, Hansen PBL, Saeb-Parsy K, and Woollard KJ
- Subjects
- 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, Phenotype, Acute Kidney Injury metabolism, Acute Kidney Injury pathology, Acute Kidney Injury etiology
- Abstract
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.)
- Published
- 2024
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