Department of Nephrology, Tangdu Hospital, Air Force Military Medical University (Fourth Military Medical University), Xi'an, 710038, China.
Department of Cardiology, Tangdu Hospital, Air Force Military Medical University (Fourth Military Medical University), Xi'an, 710038, China.
Mol Med. 2023 Apr 3;29(1):42. doi: 10.1186/s10020-023-00642-5.
Ferroptosis, which is characterized by lipid peroxidation and iron accumulation, is closely associated with the pathogenesis of acute renal injury (AKI). Cyanidin-3-glucoside (C3G), a typical flavonoid that has anti-inflammatory and antioxidant effects on ischemia‒reperfusion (I/R) injury, can induce AMP-activated protein kinase (AMPK) activation. This study aimed to show that C3G exerts nephroprotective effects against I/R-AKI related ferroptosis by regulating the AMPK pathway.
Hypoxia/reoxygenation (H/R)-induced HK-2 cells and I/R-AKI mice were treated with C3G with or without inhibiting AMPK. The level of intracellular free iron, the expression of the ferroptosis-related proteins acyl-CoA synthetase long chain family member 4 (ACSL4) and glutathione peroxidase 4 (GPX4), and the levels of the lipid peroxidation markers 4-hydroxynonenal (4-HNE), lipid reactive oxygen species (ROS) and malondialdehyde (MDA) were examined.
We observed the inhibitory effect of C3G on ferroptosis in vitro and in vivo, which was characterized by the reversion of excessive intracellular free iron accumulation, a decrease in 4-HNE, lipid ROS, MDA levels and ACSL4 expression, and an increase in GPX4 expression and glutathione (GSH) levels. Notably, the inhibition of AMPK by CC significantly abrogated the nephroprotective effect of C3G on I/R-AKI models in vivo and in vitro.
Our results provide new insight into the nephroprotective effect of C3G on acute I/R-AKI by inhibiting ferroptosis by activating the AMPK pathway.
铁死亡是一种脂质过氧化和铁积累为特征的过程，与急性肾损伤（AKI）的发病机制密切相关。矢车菊素-3-葡萄糖苷（C3G）是一种典型的黄酮类化合物，对缺血再灌注（I/R）损伤具有抗炎和抗氧化作用，可诱导 AMP 激活蛋白激酶（AMPK）的激活。本研究旨在表明 C3G 通过调节 AMPK 通路对 I/R-AKI 相关铁死亡发挥肾脏保护作用。
用 C3G 处理缺氧/复氧（H/R）诱导的 HK-2 细胞和 I/R-AKI 小鼠，并用或不用抑制 AMPK。检测细胞内游离铁水平、铁死亡相关蛋白酰基辅酶 A 合成酶长链家族成员 4（ACSL4）和谷胱甘肽过氧化物酶 4（GPX4）的表达，以及脂质过氧化标志物 4-羟壬烯醛（4-HNE）、脂质活性氧（ROS）和丙二醛（MDA）的水平。
我们观察到 C3G 在体外和体内对铁死亡的抑制作用，其特征是过量的细胞内游离铁积累得到逆转，4-HNE、脂质 ROS、MDA 水平和 ACSL4 表达降低，GPX4 表达和谷胱甘肽（GSH）水平升高。值得注意的是，CC 抑制 AMPK 显著削弱了 C3G 对体内和体外 I/R-AKI 模型的肾脏保护作用。
我们的研究结果为 C3G 通过激活 AMPK 通路抑制铁死亡对急性 I/R-AKI 的肾脏保护作用提供了新的见解。
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