Department of Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University, Harbin Medical University, Harbin, Heilongjiang 150001, People's Republic of China.
Department of Critical Care Medicine, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin, Heilongjiang 150081, People's Republic of China.
Drug Des Devel Ther. 2021 Feb 11;15:501-513. doi: 10.2147/DDDT.S294266. eCollection 2021.
Sepsis, a destructive inflammatory response syndrome, is the principal reason to induce death in the intensive care unit. Loganin has been proved to possess the property of anti-inflammation, antioxidant, neuroprotection, and sedation. The primary aim of this study was to evaluate whether Loganin could alleviate acute kidney injury (AKI) during sepsis and investigate the latent mechanisms.
Septic AKI models were established by cecal ligation and puncture (CLP) surgery in mice and given Loganin (20, 40, 80 mg/kg) by gavage. Lipopolysaccharides (LPS)-stimulated human kidney proximal tubular (HK2) cells incubated in Loganin (5, 10, 20 μ M) were used to explore the accurate mechanisms. Survival rate, renal function (creatinine and blood urea nitrogen), and renal pathological changes were detected in septic mice. Oxidative stress markers (SOD, GSH-Px, MDA, and SOD), mitochondrial membrane potential, mitochondrial calcium overload, and nuclear factor E2-related factor 2 (Nrf2)/heme-oxygenase 1 (HO-1) pathway activation in vivo and in vitro were determined by commercial kits and Western blot. Cell apoptosis, apoptotic-related protein (cleaved caspase-3, Bcl-2, and Bax) expression and protein kinase B (AKT) phosphorylation in vivo and in vitro were measured by TUNEL staining and Western blot. Finally, AKT blockage by 10 μM LY294002 or Nrf2 inhibition by10 μ M ML385 were utilized to prove the involvement of AKT and Nrf2/HO-1 pathway in AKI during sepsis.
We found Loganin treatment (20, 40, 80 mg/kg) mitigated septic AKI reflected by elevated renal function and palliative pathological changes. Oxidative stress and apoptosis in the kidney and LPS-treated HK2 cells were also inhibited by Loganin administration, which was accompanied by AKT and Nrf2/HO-1 pathway activation. Besides, the protective effects of Loganin could be diminished by AKT or Nrf2 blockage, indicating the involvement of AKT and Nrf2/HO-1 pathway.
The results suggested that the protective effects of Loganin on AKI during sepsis might be mediated by AKT and Nrf2/HO-1 pathway signaling activation in kidney proximal tubular cells.
脓毒症是一种破坏性的炎症反应综合征，是导致重症监护病房死亡的主要原因。马钱苷已被证明具有抗炎、抗氧化、神经保护和镇静作用。本研究的主要目的是评估马钱苷是否能减轻脓毒症引起的急性肾损伤（AKI），并探讨潜在的机制。
通过盲肠结扎穿孔（CLP）手术建立脓毒症 AKI 模型，并用马钱苷（20、40、80mg/kg）灌胃。用马钱苷（5、10、20μM）孵育脂多糖（LPS）刺激的人肾近端小管（HK2）细胞，探讨确切机制。检测脓毒症小鼠的生存率、肾功能（肌酐和血尿素氮）和肾脏病理变化。采用商业试剂盒和 Western blot 测定体内和体外氧化应激标志物（SOD、GSH-Px、MDA 和 SOD）、线粒体膜电位、线粒体钙超载和核因子 E2 相关因子 2（Nrf2）/血红素加氧酶 1（HO-1）通路的激活。通过 TUNEL 染色和 Western blot 测定体内和体外细胞凋亡、凋亡相关蛋白（cleaved caspase-3、Bcl-2 和 Bax）表达和蛋白激酶 B（AKT）磷酸化。最后，用 10μM LY294002 阻断 AKT 或用 10μM ML385 抑制 Nrf2 来证明 AKT 和 Nrf2/HO-1 通路在脓毒症期间 AKI 中的作用。
我们发现，马钱苷（20、40、80mg/kg）治疗可改善脓毒症 AKI ，表现为肾功能升高和病理变化缓解。马钱苷还可抑制肾脏和 LPS 处理的 HK2 细胞中的氧化应激和凋亡，同时激活 AKT 和 Nrf2/HO-1 通路。此外，AKT 或 Nrf2 阻断可减弱马钱苷的保护作用，表明 AKT 和 Nrf2/HO-1 通路的参与。
结果表明，马钱苷对脓毒症 AKI 的保护作用可能是通过激活肾脏近端小管细胞中的 AKT 和 Nrf2/HO-1 通路信号来介导的。
