van der Aart T J, Molema G, Jongman R M, Bouma H R, Koeze J, Moser J, van Londen M, Hackl M, Diendorfer A B, Ter Maaten J C, van Meurs M, Luxen M
Department of Internal Medicine, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands.
Department of Acute Care, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Intensive Care Med Exp. 2025 Sep 2;13(1):92. doi: 10.1186/s40635-025-00801-4.
Endothelial cells play a central role in the pathophysiology of sepsis-associated acute kidney injury (SA-AKI), yet we have limited understanding of the markers of microvascular-specific response. We therefore employed a translational approach integrating spatially resolved transcriptomics in a mouse SA-AKI model with validation in human kidney tissues and plasma, aiming to define the molecular signature of the endothelial response to SA-AKI in mice and in human patients.
In this post hoc analysis of prospectively collected data, we identified sepsis-associated target mRNAs and validated their expression via RT-qPCR in distinct renal microvascular compartments isolated by laser microdissection (LMD) from both cecal ligation and puncture (CLP) mice and post-mortem kidney biopsies of SA-AKI patients. Additionally, we measured the corresponding circulating proteins in plasma from two patient cohorts with sepsis and SA-AKI: one consisting of patients presenting to the emergency department, and the other of patients with severe sepsis requiring organ support in the ICU.
We identified several differentially expressed genes in the renal microvasculature following sepsis, including Mt1, Mt2, Saa3, Hp, C3, Sparc, Mmp8, and Chil3. Whole-organ samples from CLP mice also showed increased expression in the liver and lung. Except for SPARC, all genes were similarly upregulated in human kidney biopsies from SA-AKI patients. Circulating protein levels were elevated in sepsis and SA-AKI patients compared to controls; however, only CHI3L1 and MMP8 showed significantly higher levels in SA-AKI versus sepsis across both early and advanced stages.
Our findings reveal markers of the microvascular response to sepsis, which include increased levels of HP, C3, Chil3/CHI3L1, and MMP8, both at the transcriptomic level in mouse and human kidney microvasculature and at the protein level in circulating plasma of SA-AKI patients. The upregulation of these markers was shared across multiple organs and may reflect widespread endothelial activation contributing to sepsis pathophysiology.
内皮细胞在脓毒症相关急性肾损伤（SA-AKI）的病理生理学中起核心作用，但我们对微血管特异性反应的标志物了解有限。因此，我们采用了一种转化方法，将小鼠SA-AKI模型中的空间分辨转录组学与人类肾组织和血浆中的验证相结合，旨在确定小鼠和人类患者中内皮细胞对SA-AKI反应的分子特征。
在对前瞻性收集的数据进行的这项事后分析中，我们鉴定了脓毒症相关的靶mRNA，并通过RT-qPCR在从盲肠结扎和穿刺（CLP）小鼠以及SA-AKI患者的尸检肾活检组织中通过激光显微切割（LMD）分离的不同肾微血管区室中验证了它们的表达。此外，我们测量了来自两个脓毒症和SA-AKI患者队列的血浆中相应的循环蛋白：一个队列由急诊科就诊的患者组成，另一个队列由重症监护病房中需要器官支持的严重脓毒症患者组成。
我们在脓毒症后肾微血管中鉴定了几个差异表达的基因，包括Mt-1、Mt-2、Saa3、Hp、C3、Sparc、Mmp8和Chil3。CLP小鼠的全器官样本在肝脏和肺中也显示出表达增加。除了SPARC外，所有基因在SA-AKI患者的人类肾活检组织中也有类似的上调。与对照组相比，脓毒症和SA-AKI患者的循环蛋白水平升高；然而，在早期和晚期，只有CHI3L1和MMP-8在SA-AKI患者中的水平显著高于脓毒症患者。
我们的研究结果揭示了微血管对脓毒症反应的标志物，包括小鼠和人类肾微血管转录组水平以及SA-AKI患者循环血浆蛋白水平上的Hp、C3、Chil3/CHI3L1和MMP-8水平升高。这些标志物的上调在多个器官中都存在，可能反映了广泛的内皮细胞激活，这对脓毒症病理生理学有影响。
