School of Pharmacy, Fudan University, Shanghai, 201203, China.
Acta Pharmacol Sin. 2023 Aug;44(8):1676-1686. doi: 10.1038/s41401-023-01064-z. Epub 2023 Mar 1.
Diabetic kidney disease (DKD) is a common microvascular complication of diabetes mellitus, and oxidative stress and mitochondrial dysfunction play an important role in this process. It has been shown that aldose reductase (ALR2) catalyzes NADPH-dependent reduction of glucose to sorbitol, resulting in oxidative stress and mitochondrial dysfunction in diabetic patients. Astragalin (AG), a flavonoid extracted from Thesium chinense Turcz., shows an inhibitory activity on ALR2. In this study, we investigated the therapeutic effects of AG against renal injury in streptozocin (STZ)-induced diabetic mouse model. Diabetic mice were orally administered AG (5, 10 mg·kg·d) for 4 weeks. We showed that AG treatment greatly improved the proteinuria and ameliorated renal pathological damage without affecting the elevated blood glucose in diabetic mice. Furthermore, AG treatment significantly suppressed highly activated ALR2, and reduced oxidative stress in the kidney of diabetic mice and in high glucose and lipids-stimulated HK2 cells in vitro. We demonstrated that AG treatment modulated mitochondrial quality control and ameliorated apoptosis, boosting mitochondrial biogenesis, maintaining mitochondrial dynamic homeostasis, and improving energy metabolism disorder in vivo and in vitro. In high glucose and lipids-stimulated HK2 cells, we found that AG (20 μM) restored the phosphorylation level of AMPK, and upregulated the expression and transcriptional activity of PGC1α, whereas treatment with HO, blockade of AMPK with Compound C or knockdown of AMPKα with siRNA abolished the protective effect of AG on mitochondrial function, suggesting that antioxidant effects and activation of AMPK-dependent PGC1α pathway might be the molecular mechanisms underlying the protective effects of AG on mitochondrial quality control. We conclude that AG could be a promising drug candidate for the treatment of diabetic renal injury through activating AMPK.
糖尿病肾病（DKD）是糖尿病的一种常见微血管并发症，氧化应激和线粒体功能障碍在此过程中起重要作用。研究表明醛糖还原酶（ALR2）可催化 NADPH 依赖性将葡萄糖还原为山梨醇，导致糖尿病患者发生氧化应激和线粒体功能障碍。来自苍耳属植物的黄酮类化合物毛蕊异黄酮（AG）对 ALR2 具有抑制活性。在这项研究中，我们研究了 AG 对链脲佐菌素（STZ）诱导的糖尿病小鼠模型肾损伤的治疗作用。糖尿病小鼠经口给予 AG（5、10mg·kg·d）4 周。结果表明，AG 治疗可显著改善蛋白尿并改善肾脏病理损伤，而不影响糖尿病小鼠升高的血糖。此外，AG 治疗可显著抑制高度激活的 ALR2，并减少糖尿病小鼠肾脏和体外高糖高脂刺激的 HK2 细胞中的氧化应激。我们证明 AG 治疗可调节线粒体质量控制并改善凋亡，促进线粒体生物发生，维持线粒体动态平衡，并改善体内和体外的能量代谢紊乱。在高糖高脂刺激的 HK2 细胞中，我们发现 AG（20μM）可恢复 AMPK 的磷酸化水平，并上调 PGC1α 的表达和转录活性，而用 HO、用 Compound C 阻断 AMPK 或用 siRNA 敲低 AMPKα 则消除了 AG 对线粒体功能的保护作用，表明抗氧化作用和 AMPK 依赖性 PGC1α 通路的激活可能是 AG 对线粒体质量控制的保护作用的分子机制。我们得出结论，AG 可能通过激活 AMPK 成为治疗糖尿病肾病的有前途的药物候选物。
