Multi-omics and imaging mass cytometry characterization of human kidneys to identify pathways and phenotypes associated with impaired kidney function.
Multi-omics and imaging mass cytometry characterization of human kidneys to identify pathways and phenotypes associated with impaired kidney function.
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DOI：
10.1016/j.kint.2024.01.041
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发表时间：
2024-02
影响因子：
19.6
通讯作者：
E. Asowata;Simone Romoli;Rebecca Sargeant;Jennifer Y. Tan;Scott Hoffmann;Margaret M. Huang;Krishnaa T. Mahbubani;Fynn N. Krause;Daniel Jachimowicz;Rasmus Ågren;Albert Koulman;Benjamin Jenkins;Barbara Musial;Julian L. Griffin;Magnus Soderberg;Stephanie Ling;Pernille B. L. Hansen;K. Saeb‐Parsy;Kevin J. Woollard
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文献类型：
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作者：
E. Asowata;Simone Romoli;Rebecca Sargeant;Jennifer Y. Tan;Scott Hoffmann;Margaret M. Huang;Krishnaa T. Mahbubani;Fynn N. Krause;Daniel Jachimowicz;Rasmus Ågren;Albert Koulman;Benjamin Jenkins;Barbara Musial;Julian L. Griffin;Magnus Soderberg;Stephanie Ling;Pernille B. L. Hansen;K. Saeb‐Parsy;Kevin J. Woollard
尽管最近我们对脂质、代谢物和相关酶在介导肾损伤中的作用的理解有所进展，但识别潜在代谢途径驱动肾功能受损的综合多组学数据有限。急性肾损伤活体供者肾活检的有限可用性仍然是一个主要制约因素。在这里，我们验证了使用已故移植供体肾脏作为研究人类急性肾损伤的良好模型，并使用成像和多组学方法对这些肾脏进行了表征。我们注意到肾功能降低的供者肾损伤和炎症标志物的一致变化。成像细胞术数据的邻域分析和相关分析显示，肾细胞亚群（近端小管细胞和成纤维细胞）与肾免疫细胞的表达谱相关，可能将这些细胞与肾脏炎症联系起来。人体肾脏的综合转录组学和代谢组学分析显示，肾脏花生四烯酸代谢和其他7种代谢途径在肾功能减弱后上调。为了验证花生四烯酸途径在肾功能受损中的作用，我们证实损伤肾脏中胞质磷脂酶A2蛋白和相关脂质介质（前列腺素E2）水平升高。此外，抑制胞质磷脂酶A2可减少体外人肾近端小管上皮细胞的损伤和炎症。因此，我们的研究确定了细胞类型和代谢途径，它们可能对控制与人类肾功能受损相关的炎症至关重要。
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 cellsin vitro. Thus, our study identified cell types and metabolic pathways that may be critical for controlling inflammation associated with impaired kidney function in humans.