School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan, China.
School of Life Sciences, Nanjing University, Nanjing, China.
J Ethnopharmacol. 2024 Dec 5;335:118648. doi: 10.1016/j.jep.2024.118648. Epub 2024 Jul 31.
Ischemia-reperfusion (IR) injury can result in acute renal failure. Oxidative stress is a major factor in IR-induced cell death in the kidneys. According to traditional Chinese medicine, earthworms (Pheretima aspergillum) can be used to treat various kidney diseases.
The present study was designed to understand the protective effects of the water extract of earthworms (WEE) against oxidative stress on the kidneys and the crucial molecular events associated with its nephroprotective activity.
Cytotoxicity caused by HO in HEK293, HK2, and primary mouse renal tubular epithelial cells (TECs) was used to investigate the effect of WEE on oxidative stress-induced renal injury in vitro. IR-induced kidney injury was established using rats as an in vivo model. The WEE-mediated protection of the kidneys against oxidative stress was compared with that of glutathione, a common antioxidant used as a positive control.
In HEK293 cells, HK2 cells, and primary mouse TECs, WEE relieved HO-induced mitochondrial damage, apoptosis, and ferroptosis. In kidney cells, WEE increased the expression of Sirt1, boosted LKB1 and AMPK phosphorylation, and upregulated nuclear Nrf2. Suppression of Sirt1 and LKB1 knock down abrogated WEE-induced protection against HO. WEE ameliorated IR-induced kidney injury and intrarenal inflammation in rats. In rat kidneys, WEE mitigated mitochondrial damage and suppressed IR-induced apoptosis and ferroptosis. Mechanistically, WEE increased Sirt1 expression, enhanced the phosphorylation of LKB1 and AMPK, and increased intranuclear Nrf2 levels in IR kidneys. IR treatment resulted in considerable increase in renal MDA levels and a prominent decrease in antioxidative enzyme activity. These lesions were significantly alleviated by WEE.
WEE mitigated HO-induced cytotoxicity in kidney cells in vitro and improved IR-induced kidney damage in rats. Mechanistically, WEE potentiated the Sirt1/Nrf2 axis and relieved mitochondrial damage in the kidney cells. These events inhibited the apoptosis and ferroptosis induced by oxidative stress. Our findings support the potential application of WEE for the clinical treatment of kidney diseases caused by intrarenal oxidative stress.
缺血再灌注（IR）损伤可导致急性肾衰竭。氧化应激是肾脏中 IR 诱导细胞死亡的一个主要因素。根据中医理论，蚯蚓（环毛蚓）可用于治疗各种肾脏疾病。
本研究旨在了解蚯蚓水提物（WEE）对肾脏氧化应激的保护作用及其对肾脏保护活性相关关键分子事件的影响。
用 HO 在 HEK293、HK2 和原代小鼠肾小管上皮细胞（TECs）中引起的细胞毒性来研究 WEE 对体外氧化应激诱导的肾损伤的影响。用大鼠建立 IR 诱导的肾损伤模型。将 WEE 对氧化应激的肾脏保护作用与作为阳性对照的常用抗氧化剂谷胱甘肽进行比较。
在 HEK293 细胞、HK2 细胞和原代小鼠 TECs 中，WEE 缓解了 HO 诱导的线粒体损伤、凋亡和铁死亡。在肾细胞中，WEE 增加了 Sirt1 的表达，促进了 LKB1 和 AMPK 的磷酸化，并上调了核 Nrf2。Sirt1 和 LKB1 的抑制敲除削弱了 WEE 对 HO 的保护作用。WEE 改善了大鼠 IR 诱导的肾损伤和肾内炎症。在大鼠肾脏中，WEE 减轻了线粒体损伤，并抑制了 IR 诱导的凋亡和铁死亡。机制上，WEE 增加了 Sirt1 的表达，增强了 LKB1 和 AMPK 的磷酸化，并增加了 IR 肾脏中的核 Nrf2 水平。IR 处理导致肾 MDA 水平显著升高，抗氧化酶活性显著降低。WEE 显著减轻了这些病变。
WEE 减轻了体外肾细胞中 HO 诱导的细胞毒性，并改善了大鼠 IR 诱导的肾损伤。机制上，WEE 增强了 Sirt1/Nrf2 轴，减轻了肾脏细胞中的线粒体损伤。这些事件抑制了氧化应激诱导的细胞凋亡和铁死亡。我们的研究结果支持 WEE 在临床上治疗由肾内氧化应激引起的肾脏疾病的应用潜力。
