Berberine enhances the AMPK activation and autophagy and mitigates high glucose-induced apoptosis of mouse podocytes
Berberine enhances the AMPK activation and autophagy and mitigates high glucose-induced apoptosis of mouse podocytes
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DOI：
10.1016/j.ejphar.2016.11.037
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发表时间：
2017-01-05
影响因子：
5
通讯作者：
Chen, Li
中科院分区：
文献类型：
--
作者：
Jin, Yingli;Liu, Shuping;Chen, Li
高糖可导致足细胞损伤，小檗碱具有较强的抗糖尿病肾病作用。然而，黄连素是否以及如何抑制高糖介导的足细胞损伤尚不清楚。本研究检测了黄连素对高糖诱导的足细胞凋亡及哺乳动物雷帕霉素(MTOR)靶蛋白AMPK活化和自噬的影响。结果表明，黄连素能显著减轻高糖所致的小鼠足细胞存活率下降，并能明显减轻细胞内neparin和podocin的表达以及细胞的凋亡。黄连素显著增强足细胞AMPK活性，减轻高糖和/或AMPK抑制剂、化合物C介导的mTOR激活和足细胞凋亡。黄连素显著增强AMPK的激活，并对高糖诱导的AMPK沉默足细胞的凋亡具有保护作用。此外，黄连素显著增加高糖刺激的足细胞UNC-51样自噬激活蛋白1(ULK1)S317/S555的磷酸化、Beclin-1的表达、LC3II/LC3I的表达比值和自噬小体数目，但降低足细胞ULK1 S757的磷酸化。此外，黄连素显著减弱化合物C对足细胞自噬的抑制作用。黄连素对高糖诱导的足细胞凋亡的保护作用可被3-甲基腺嘌呤或巴菲霉素A1预先处理显著减轻。总的来说，黄连素通过促进AMPK的激活来增强足细胞的自噬，并保护其免受高糖诱导的损伤。我们的发现可能为黄连素抗糖尿病肾病作用的分子机制提供新的见解，并可能有助于设计干预糖尿病肾病的新疗法。
High glucose concentration can induce injury of podocytes and berberine has a potent activity against diabetic nephropathy. However, whether and how berberine can inhibit high glucose-mediated injury of podocytes have not been clarified. This study tested the effect of berberine on high glucose-mediated apoptosis and the AMPactivated protein kinase (AMPK), mammalian target of rapamycin (mTOR) activation and autophagy in podocytes. The results indicated that berberine significantly mitigated high glucose-decreased cell viability, and nephrin and podocin expression as well as apoptosis in mouse podocytes. Berberine significantly increased the AMPK activation and mitigated high glucose and/or the AMPK inhibitor, compound C-mediated mTOR activation and apoptosis in podocytes. Berberine significantly enhanced the AMPK activation and protected from high glucose-induced apoptosis in the AMPK-silencing podocytes. Furthermore, berberine significantly increased the high glucose-elevated Unc-51-like autophagy-activating kinase 1 (ULK1) S317/S555 phosphorylation, Beclin-1 expression, the ratios of LC3II to LC3I expression and the numbers of autophagosomes, but reduced ULK1 S757 phosphorylation in podocytes. In addition, berberine significantly attenuated compound C-mediated inhibition of autophagy in podocytes. The protective effect of berberine on high glucose-induced podocyte apoptosis was significantly mitigated by pre-treatment with 3-methyladenine or bafilomycin A1. Collectively, berberine enhanced autophagy and protected from high glucose-induced injury in podocytes by promoting the AMPK activation. Our findings may provide new insights into the molecular mechanisms underlying the anti-diabetic nephropathy effect of berberine and may aid in design of new therapies for intervention of diabetic nephropathy.