Astragaloside IV protects against podocyte injury via SERCA2-dependent ER stress reduction and AMPKα-regulated autophagy induction in streptozotocin-induced diabetic nephropathy.
Astragaloside IV protects against podocyte injury via SERCA2-dependent ER stress reduction and AMPKα-regulated autophagy induction in streptozotocin-induced diabetic nephropathy.
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DOI：
10.1038/s41598-017-07061-7
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发表时间：
2017-07-31
影响因子：
4.6
通讯作者：
Peng W
中科院分区：
文献类型：
--
作者：
Guo H;Wang Y;Zhang X;Zang Y;Zhang Y;Wang L;Wang H;Wang Y;Cao A;Peng W
异常内质网应激和自噬与糖尿病肾病有关。本研究探讨了黄芪甲苷（AS-IV）对链脲佐菌素（STZ）诱导的糖尿病小鼠和高糖（HG）培养足细胞的内质网应激和自噬的影响及其机制。糖尿病小鼠在8周内出现进行性尿白蛋白和肾小球硬化，AS-IV治疗显著改善，且呈剂量依赖性。此外，AS-IV可显著减轻糖尿病或hg诱导的足细胞凋亡，同时内质网应激显著缓解，受损的自噬显著恢复，这与肌内质网Ca2+ atp酶2b （SERCA2b）和amp活化的蛋白激酶α (AMPKα)磷酸化的表达显著改善有关。足细胞中SERCA2的敲低诱导内质网应激，并在很大程度上消除AS-IV的保护作用，但对自噬相关蛋白的表达无明显影响。另一方面，阻断自噬诱导或AMPKα激活也可以显著减轻as - iv诱导的有益作用。综上所述，这些结果表明AS-IV阻止了DN的进展，这至少部分是由serca2依赖性内质网应激衰减和ampk α促进的自噬诱导介导的。
Aberrant endoplasmic reticulum (ER) stress and autophagy are associated with diabetic nephropathy. Here we investigated the effect of astragaloside IV (AS-IV) on the progression of diabetic nephropathy (DN) and the underlying mechanism involving ER stress and autophagy in streptozotocin (STZ)-induced diabetic mice and high glucose (HG)-incubated podocytes. The diabetic mice developed progressive albuminuria and glomerulosclerosis within 8 weeks, which were significantly ameliorated by AS-IV treatment in a dose-dependent manner. Moreover, diabetes or HG-induced podocyte apoptosis was markedly attenuated by AS-IV, paralleled by a marked remission in ER stress and a remarkable restoration in impaired autophagy, which were associated with a significant improvement in the expression of sarcoendoplasmic reticulum Ca2+ ATPase 2b (SERCA2b) and AMP-activated protein kinase α (AMPKα) phosphorylation, respectively. Knockdown of SERCA2 in podocytes induced ER stress and largely abolished the protective effect of AS-IV, but had no obvious effect on the expression of autophagy-associated proteins. On the other hand, blockade of either autophagy induction or AMPKα activation could also significantly mitigate AS-IV-induced beneficial effect. Collectively, these results suggest that AS-IV prevented the progression of DN, which is mediated at least in part by SERCA2-dependent ER stress attenuation and AMPKα-promoted autophagy induction.
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