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 . Thus, our study identified cell types and metabolic pathways that may be critical for controlling inflammation associated with impaired kidney function in humans.

中文翻译：

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人类肾脏的多组学和成像质谱流式分析表征，以确定与肾功能受损相关的途径和表型

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取得了进展，但识别驱动肾功能受损的潜在代谢途径的综合多组学数据有限。来自患有急性肾损伤的活体捐献者的肾活检的可用性有限仍然是一个主要限制因素。在这里，我们验证了使用死亡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。我们注意到肾功能下降的捐献者的肾损伤和炎症标志物发生了一致的变化。成像质谱流式细胞仪数据的邻域和相关分析表明，肾细胞亚群（近端肾小管细胞和成纤维细胞）与肾脏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。对人类肾脏的转录组学和代谢组学综合分析表明，肾功能减弱后，肾脏花生四烯酸代谢和其他七种代谢途径上调。为了验证受损肾功能中的花生四烯酸途径，我们证明受损肾脏中胞质磷脂酶 A2 蛋白和相关脂质介质（前列腺素 E2）的水平增加。此外，抑制胞质磷脂酶 A2 可减少人肾近端肾小管上皮细胞的损伤和炎症。因此，我们的研究确定了对于控制与人类肾功能受损相关的炎症可能至关重要的细胞类型和代谢途径。