Department of Pharmacology, School of Basic Medical Sciences, Peking University and Beijing Key Laboratory of Tumor Systems Biology, Peking University, Beijing, 100191, China; Research Center of Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China.
Department of Pharmacology, School of Basic Medical Sciences, Peking University and Beijing Key Laboratory of Tumor Systems Biology, Peking University, Beijing, 100191, China.
Eur J Pharmacol. 2022 Feb 5;916:174603. doi: 10.1016/j.ejphar.2021.174603. Epub 2021 Nov 16.
Acute kidney injury (AKI) is a serious threat to human health. Clinically, ischemia-reperfusion (I/R) injury is considered one of the most common contributors to AKI. Emodin has been reported to alleviate I/R injury in the heart, brain, and small intestine in rats and mice through its anti-inflammatory effects. The present study investigated whether emodin improved AKI induced by I/R and elucidated the molecular mechanisms. We used a mouse model of renal I/R injury and human renal tubular epithelial cell model of hypoxia/reoxygenation (H/R) injury. Ischemia/reperfusion resulted in renal dysfunction. Pretreatment with emodin ameliorated renal injury in mice following I/R injury. Emodin reduced mitochondrial-mediated apoptosis, suppressed the overproduction of mitochondrial reactive oxygen species and accelerated the recovery of adenosine triphosphate both in vivo and in vitro. Emodin prevented mitochondrial fission and restored the balance of mitochondrial dynamics. The phosphorylation of dynamin-related protein 1 (DRP1) at Ser616, a master regulator of mitochondrial fission, was upregulated in both models of I/R and H/R injury, and this upregulation was blocked by emodin. Using computational cognate protein kinase prediction and specific kinase inhibitors, we found that emodin inhibited the phosphorylation of calcium/calmodulin-dependent protein kinase II (https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1554), thereby inhibiting its kinase activity and reducing the phosphorylation of DRP1 at Ser616. The results demonstrated that emodin pretreatment could protect renal function by improving mitochondrial dysfunction induced by I/R.
急性肾损伤 (AKI) 是对人类健康的严重威胁。临床上，缺血再灌注 (I/R) 损伤被认为是导致 AKI 的最常见原因之一。已有研究报道大黄素通过其抗炎作用减轻大鼠和小鼠心脏、大脑和小肠的 I/R 损伤。本研究旨在探讨大黄素是否改善 I/R 引起的 AKI，并阐明其分子机制。我们使用了小鼠肾脏 I/R 损伤模型和人肾小管上皮细胞缺氧/复氧 (H/R) 损伤模型。I/R 导致肾功能障碍。大黄素预处理可改善 I/R 后小鼠的肾损伤。大黄素减少了线粒体介导的细胞凋亡，抑制了线粒体活性氧的过度产生，并加速了体内和体外三磷酸腺苷的恢复。大黄素防止了线粒体分裂，并恢复了线粒体动力学的平衡。在 I/R 和 H/R 损伤两种模型中，DRP1 丝氨酸 616 位点的磷酸化（线粒体分裂的主要调节因子）均上调，而大黄素可阻断这一上调。通过计算同源蛋白激酶预测和特定的激酶抑制剂，我们发现大黄素抑制钙/钙调蛋白依赖性蛋白激酶 II 的磷酸化（https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1554），从而抑制其激酶活性，并降低 DRP1 丝氨酸 616 位点的磷酸化。结果表明，大黄素预处理可通过改善 I/R 引起的线粒体功能障碍来保护肾功能。
