Purpose: 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.
Methods: 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.
Results: 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.
Conclusion: 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.

Keywords: sepsis, acute kidney injury, Loganin, AKT, Nrf2/HO-1


中文翻译：

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Loganin 在 AKT 和 Nrf2/HO-1 信号通路的参与下减轻感染性急性肾损伤

目的：脓毒症是一种破坏性炎症反应综合征，是在重症监护室导致死亡的主要原因。Loganin 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 Loganin 是否可以缓解脓毒症期间的急性肾损伤 (AKI) 并研究潜在机制。
方法：通过小鼠盲肠结扎和穿刺 (CLP) 手术建立脓毒性 AKI 模型，并通过管饲法给予 Loganin (20, 40, 80 mg/kg)。在 Loganin（5, 10, 20 μM）中孵育的脂多糖（LPS）刺激的人肾近端肾小管（HK2）细胞用于探索准确的机制。检测脓毒症小鼠的存活率、肾功能（肌酐和血尿素氮）和肾脏病理变化。体内氧化应激标志物（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) 通路激活和通过商业试剂盒和蛋白质印迹测定体外。细胞凋亡、凋亡相关蛋白（cleaved caspase-3、Bcl-2、通过 TUNEL 染色和蛋白质印迹测量体内和体外的 Bax) 表达和蛋白激酶 B (AKT) 磷酸化。最后，利用 10 μM LY294002 阻断 AKT 或通过 10 μM ML385 抑制 Nrf2 来证明 AKT 和 Nrf2/HO-1 通路在脓毒症期间参与 AKI。
结果：我们发现 Loganin 治疗（20、40、80 mg/kg）减轻了肾功能升高和姑息性病理变化所反映的脓毒性 AKI。Loganin 给药也抑制了肾脏和 LPS 处理的 HK2 细胞中的氧化应激和细胞凋亡，这伴随着 AKT 和 Nrf2/HO-1 通路的激活。此外，AKT 或 Nrf2 阻断可降低 Loganin 的保护作用，表明 AKT 和 Nrf2/HO-1 通路的参与。
结论：结果提示Loganin对脓毒症AKI的保护作用可能是通过肾脏近端肾小管细胞中AKT和Nrf2/HO-1通路信号激活介导的。

关键词：脓毒症，急性肾损伤，Loganin，AKT，Nrf2/HO-1