A major challenge in prevention and early treatment of organ fibrosis is the lack of valuable tools to assess the evolving profibrotic maladaptive repair after injury in vivo in a non-invasive way. Here, using acute kidney injury (AKI) as an example, we tested the utility of fibroblast activation protein (FAP) imaging for dynamic assessment of maladaptive repair after injury. The temporospatial pattern of kidney FAP expression after injury was first characterized. Single-cell RNA sequencing and immunostaining analysis of patient biopsies were combined to show that FAP was specifically upregulated in kidney fibroblasts after AKI and was associated with fibroblast activation and chronic kidney disease (CKD) progression. This was corroborated in AKI mouse models, where a sustained and exaggerated kidney FAP upregulation was coupled to persistent fibroblast activation and a fibrotic outcome, linking kidney FAP level to post-insult maladaptive repair. Furthermore, using positron emission tomography (PET)/CT scanning with FAP-inhibitor tracers ([18F]FAPI-42, [18F]FAPT) targeting FAP, we demonstrated the feasibility of non-invasively tracking of maladaptive repair evolution toward kidney fibrosis. Importantly, a sustained increase in kidney [18F]FAPT (less hepatobiliary metabolized than [18F]FAPI-42) uptake reflected persistent kidney upregulation of FAP and characterized maladaptive repair after AKI. Kidney [18F]FAPT uptake at hour 2-day 7 correlated with kidney fibrosis 14 days after AKI. Similar changes in [18F]FAPI-42 PET/CT imaging were observed in patients with AKI and CKD progression. Thus, persistent kidney FAP upregulation after AKI was associated with maladaptive repair and a fibrotic outcome. Hence, FAP-specific PET/CT imaging enables dynamic visualization of maladaptive repair after AKI and prediction of kidney fibrosis within a clinically actionable window.

中文翻译：

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通过成纤维细胞活化蛋白成像动态可视化急性肾损伤后促纤维化适应不良修复


器官纤维化预防和早期治疗的一个主要挑战是缺乏有价值的工具，以非侵入性方式评估损伤 后体内不断发展的促纤维化适应不良修复。在这里，以急性肾损伤 （AKI） 为例，我们测试了成纤维细胞活化蛋白 （FAP） 成像在损伤后适应不良修复动态评估中的效用。首先表征了损伤后肾脏 FAP 表达的时间空间模式。单细胞 RNA 测序和患者活检免疫染色分析相结合，显示 FAP 在 AKI 后肾成纤维细胞中特异性上调，并与成纤维细胞活化和慢性肾脏病 （CKD） 进展相关。这在 AKI 小鼠模型中得到了证实，其中持续和夸张的肾脏 FAP 上调与持续的成纤维细胞活化和纤维化结果相结合，将肾脏 FAP 水平与侮辱后适应不良修复联系起来。此外，使用靶向 FAP 的 FAP 抑制剂示踪剂 （[18F]FAPI-42， [18F]FAPT） 进行正电子发射断层扫描 （PET）/CT 扫描，我们证明了无创跟踪适应不良修复演变向肾纤维化的可行性。重要的是，肾脏 [18F] FAPT （肝胆代谢比 [18F]FAPI-42 少）摄取的持续增加反映了 FAP 的持续肾脏上调和 AKI 后适应性不良修复的特征。第 2 天 7 小时肾脏 [18F]FAPT 摄取与 AKI 后 14 天的肾纤维化相关。在 AKI 和 CKD 进展患者中观察到 [18F]FAPI-42 PET/CT 成像的类似变化。因此，AKI 后持续肾脏 FAP 上调与适应不良修复和纤维化结局相关。 因此，FAP 特异性 PET/CT 成像能够动态可视化 AKI 后适应不良的修复，并在临床可操作的窗口内预测肾纤维化。