Celastrol, a natural triterpenoid derived from Tripterygium wilfordii, possesses numerous biological effects. We investigated celastrol’s antioxidant potential through nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) and its effect on phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling, nuclear factor-kappa B (NF-κB) pathways, and extracellular signal-regulated kinase (ERK) activation in kidney ischemia-reperfusion injury (IRI) rat model. Rats were given celastrol 2 mg/kg orally for 1 week before subjection to renal ischemia-reperfusion surgery. Kidney functions, renal MDA, and reduced glutathione were determined; also, renal levels of ERK1/2, HO-1, PI3K, IL-6, TNF-α, IκBα, NF-κB/p65, and cleaved caspase-3 were measured. In addition, gene expression of kidney injury molecule-1 (KIM-1), Nrf-2, and AKT were determined. Celastrol pretreatment attenuated oxidative stress and increased Nrf2 gene expression and HO-1 level. Also, it activated the PI3K/AKT signaling pathway and decreased the p-ERK:t- ERK ratio and NFκBp65 level, with a remarkable decrease in inflammatory cytokines and cleaved caspase-3 levels compared with those in renal IRI rats. Conclusively, celastrol showed a reno-protective potential against renal IRI by suppressing oxidative stress through enhancing the Nrf2/HO-1 pathway, augmenting cell survival PI3K/AKT signaling pathways, and reducing inflammation by inhibiting NF-κB activation.

Celastrol 是一种源自雷公藤的天然三萜类化合物，具有多种生物效应。我们通过核因子红细胞 2 相关因子 2 (Nrf2)/血红素加氧酶 1 (HO-1) 研究了 celastrol 的抗氧化潜力及其对磷酸肌醇 3-激酶 (PI3K)/蛋白激酶 B (AKT) 信号传导、核因子-kappa 的影响B (NF-κB) 通路和肾缺血再灌注损伤 (IRI) 大鼠模型中的细胞外信号调节激酶 (ERK) 激活。在进行肾缺血再灌注手术前，大鼠口服 2 mg/kg celastrol 1 周。测定肾功能、肾MDA和还原型谷胱甘肽；此外，还测量了 ERK1/2、HO-1、PI3K、IL-6、TNF-α、IκBα、NF-κB/p65 和切割的 caspase-3 的肾脏水平。此外，肾损伤分子-1 (KIM-1)、Nrf-2、和 AKT 已确定。Celastrol 预处理减弱了氧化应激并增加了 Nrf2 基因表达和 HO-1 水平。此外，它激活了 PI3K/AKT 信号通路，降低了 p-ERK:t-ERK 比值和 NFκBp65 水平，与肾 IRI 大鼠相比，炎性细胞因子和裂解的 caspase-3 水平显着降低。最终，celastrol 通过增强 Nrf2/HO-1 通路抑制氧化应激、增加细胞存活 PI3K/AKT 信号通路和通过抑制 NF-κB 活化减少炎症，显示出对肾脏 IRI 的肾脏保护潜力。与肾 IRI 大鼠相比，炎症细胞因子和裂解的 caspase-3 水平显着降低。最终，celastrol 通过增强 Nrf2/HO-1 通路抑制氧化应激、增加细胞存活 PI3K/AKT 信号通路以及通过抑制 NF-κB 活化减少炎症，显示出对肾脏 IRI 的肾脏保护潜力。与肾 IRI 大鼠相比，炎症细胞因子和裂解的 caspase-3 水平显着降低。最终，celastrol 通过增强 Nrf2/HO-1 通路抑制氧化应激、增加细胞存活 PI3K/AKT 信号通路和通过抑制 NF-κB 活化减少炎症，显示出对肾脏 IRI 的肾脏保护潜力。