Institut für Translationale Physiologie (CCM), Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117, Berlin, Germany.
Medizinische Klinik m.S. Nephrologie und Internistische Intensivmedizin (CCM), Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117, Berlin, Germany.
Pflugers Arch. 2024 Oct;476(10):1571-1585. doi: 10.1007/s00424-024-02987-0. Epub 2024 Jul 23.
Advanced glycation endproducts (AGEs) contribute to cellular damage of various pathologies, including kidney diseases. Acute kidney injury (AKI) represents a syndrome seldom characterized by a single, distinct pathophysiological cause. Rhabdomyolysis-induced acute kidney injury (RIAKI) constitutes roughly 15% of AKI cases, yet its underlying pathophysiology remains poorly understood. Using a murine model of RIAKI induced by muscular glycerol injection, we observed elevated levels of AGEs and the AGE receptor galectin-3 (LGALS3) in the kidney. Immunofluorescence localized LGALS3 to distal nephron segments. According to transcriptomic profiling via next-generation sequencing, RIAKI led to profound changes in kidney metabolism, oxidative stress, and inflammation. Cellular stress was evident in both proximal and distal tubules, as shown by kidney injury markers KIM-1 and NGAL. However, only proximal tubules exhibited overt damage and apoptosis, as detected by routine morphology, active Caspase-3, and TUNEL assay, respectively. In vitro, distal convoluted tubule (DCT) cells challenged with AGEs underwent apoptosis, which was markedly enhanced by Lgals3 siRNA treatment. Thus, in RIAKI, the upregulation of LGALS3 may protect the distal nephron from AGE-mediated damage, while proximal tubules lacking LGALS3 stay at risk. Thus, stimulating LGALS3 in the proximal nephron, if achievable, may attenuate RIAKI.
晚期糖基化终产物（AGEs）导致多种病理的细胞损伤，包括肾脏疾病。急性肾损伤（AKI）是一种很少由单一、明确的病理生理原因引起的综合征。横纹肌溶解症引起的急性肾损伤（RIAKI）约占 AKI 病例的 15%，但其潜在的病理生理学仍知之甚少。使用肌肉甘油注射诱导的 RIAKI 小鼠模型，我们观察到肾脏中 AGEs 和 AGE 受体半乳糖凝集素-3（LGALS3）水平升高。免疫荧光将 LGALS3 定位到远端肾单位。根据下一代测序的转录组分析，RIAKI 导致肾脏代谢、氧化应激和炎症发生深刻变化。近端和远端小管均存在细胞应激，如肾损伤标志物 KIM-1 和 NGAL 所示。然而，只有近端小管表现出明显的损伤和细胞凋亡，分别通过常规形态学、活性 Caspase-3 和 TUNEL 检测来检测。在体外，用 AGEs 处理的远端连接段（DCT）细胞发生凋亡，而 Lgals3 siRNA 处理则显著增强了这种凋亡。因此，在 RIAKI 中，LGALS3 的上调可能会保护远端肾单位免受 AGE 介导的损伤，而缺乏 LGALS3 的近端肾小管则处于危险之中。因此，如果可行，刺激近端肾单位的 LGALS3 可能会减轻 RIAKI。
