Wang Bingqing, Wang Jiabei, Qi Chen, Gao Chao, Wang Yue, Zan Yujie, Tan Yuwei, Wu Zhenying, Jiang Jun, Suo Jinmeng, Zhang Jing, Peng Zhiyong
Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Hubei, 430071, Wuhan, China.
Department of Neurology, Renmin Hospital of Wuhan University, 99 Zhangzhidong Road, Hubei, 430060, Wuhan, China.
Mol Med. 2025 Sep 26;31(1):296. doi: 10.1186/s10020-025-01352-w.
Acute kidney injury (AKI) is a common complication among critically ill patients, associated with an increased risk of adverse outcomes. There is an urgent need for novel biomarkers to assist in the early detection and management of AKI. Soluble urokinase plasminogen activator receptor (suPAR) is an inflammation-related, immune-derived molecule implicated in the pathogenesis of several diseases, including kidney diseases.
We characterized the ability of serum suPAR levels to diagnose AKI in 124 patients admitted to the intensive care unit (ICU). Additionally, in vivo and in vitro experiments were performed to explore the underlying mechanisms between suPAR and the development of AKI. We stimulated HK-2 cells with suPAR to investigate its effects on HK-2 cells. Additionally, Methods such as receptor inhibitors, protein docking, and co—immunoprecipitation were used to study how suPAR acts on HK-2 cells. We further explored whether the uPAR monoclonal antibody could alleviate acute kidney injury in septic mice.
We found that serum suPAR levels were significantly elevated in patients with AKI. In addition, total suPAR/uPAR was elevated in the renal cortex of AKI mice, and serum suPAR levels were also increased. In vitro cell experiments demonstrated that suPAR stimulation promoted endoplasmic reticulum stress (ER stress) and the expression of apoptosis—related proteins in HK-2 cells and increased intracellular reactive oxygen species (ROS). Consistently, mice injected intraperitoneally with recombinant suPAR also exhibited elevated ER stress in the renal cortex. Furthermore, we discovered that suPAR was immunoprecipitated with the receptor of advanced glycation end products (RAGE), and recombinant suPAR labeled with FITC was fluorescently colocalized with RAGE on HK-2 cells, indicating that RAGE was involved in the signal transduction of suPAR. Additionally, protein docking results showed that suPAR can form a protein–protein complex with RAGE through hydrogen bonds. Pretreatment with uPAR monoclonal antibody alleviated kidney injury in septic mice and reduced the levels of ROS, apoptosis, and endoplasmic reticulum stress in the kidneys of septic AKI mice.
Our study demonstrates that high levels of suPAR are positively correlated with the occurrence of AKI. suPAR promotes endoplasmic reticulum stress and increases susceptibility to apoptosis in renal tubular epithelial cells. RAGE on the cell membrane can bind to suPAR, participating in the activation of suPAR-mediated endoplasmic reticulum stress pathways and the expression of apoptosis-related proteins. Pretreatment with uPAR monoclonal antibody alleviates acute kidney injury in septic mice.
The online version contains supplementary material available at 10.1186/s10020-025-01352-w.
急性肾损伤（AKI）是危重症患者常见的并发症，与不良预后风险增加相关。迫切需要新型生物标志物来协助AKI的早期检测和管理。可溶性尿激酶型纤溶酶原激活物受体（suPAR）是一种与炎症相关的免疫衍生分子，涉及包括肾脏疾病在内的多种疾病的发病机制。
我们对124例入住重症监护病房（ICU）的患者血清suPAR水平诊断AKI的能力进行了特征分析。此外，进行了体内和体外实验，以探讨suPAR与AKI发生发展之间的潜在机制。我们用suPAR刺激HK-2细胞，以研究其对HK-2细胞的影响。此外，还使用了受体抑制剂、蛋白质对接和免疫共沉淀等方法来研究suPAR如何作用于HK-2细胞。我们进一步探讨了uPAR单克隆抗体是否能减轻脓毒症小鼠的急性肾损伤。
我们发现AKI患者血清suPAR水平显著升高。此外，AKI小鼠肾皮质中总suPAR/uPAR升高，血清suPAR水平也升高。体外细胞实验表明，suPAR刺激可促进HK-2细胞内质网应激（ER应激）和凋亡相关蛋白的表达，并增加细胞内活性氧（ROS）水平。一致地，腹腔注射重组suPAR的小鼠肾皮质中ER应激也升高。此外，我们发现suPAR与晚期糖基化终末产物受体（RAGE）发生免疫沉淀，用异硫氰酸荧光素（FITC）标记的重组suPAR与HK-2细胞上的RAGE荧光共定位，表明RAGE参与了suPAR的信号转导。此外，蛋白质对接结果显示，suPAR可通过氢键与RAGE形成蛋白质-蛋白质复合物。用uPAR单克隆抗体预处理可减轻脓毒症小鼠的肾损伤，并降低脓毒症AKI小鼠肾脏中ROS、凋亡和内质网应激水平。
我们的研究表明，高水平的suPAR与AKI的发生呈正相关。suPAR促进内质网应激，增加肾小管上皮细胞对凋亡的易感性。细胞膜上的RAGE可与suPAR结合，参与激活suPAR介导的内质网应激途径和凋亡相关蛋白的表达。用uPAR单克隆抗体预处理可减轻脓毒症小鼠的急性肾损伤。
在线版本包含可在10.1186/s10020-025-01352-w获取的补充材料。
