Laboratory of Renal Disease, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China.
Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China.
Sci Rep. 2017 Jul 31;7(1):6852. doi: 10.1038/s41598-017-07061-7.
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 Ca 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.
内质网应激和自噬与糖尿病肾病有关。在这里，我们研究了黄芪甲苷 IV（AS-IV）对链脲佐菌素（STZ）诱导的糖尿病小鼠和高糖（HG）孵育的足细胞中糖尿病肾病（DN）进展的影响及其涉及内质网应激和自噬的潜在机制。在 8 周内，糖尿病小鼠出现进行性白蛋白尿和肾小球硬化，而 AS-IV 治疗以剂量依赖的方式显著改善了这些病变。此外，AS-IV 显著减轻了糖尿病或 HG 诱导的足细胞凋亡，内质网应激明显缓解，受损的自噬明显恢复，这与肌浆内质网 Ca ATP 酶 2b（SERCA2b）和 AMP 激活蛋白激酶α（AMPKα）磷酸化表达的显著改善相关，分别。在足细胞中敲低 SERCA2 会诱导内质网应激，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没有明显影响。另一方面，自噬诱导或 AMPKα 激活的阻断也可显著减轻 AS-IV 诱导的有益作用。总之，这些结果表明，AS-IV 可预防 DN 的进展，至少部分是通过 SERCA2 依赖性内质网应激缓解和 AMPKα 促进自噬诱导介导的。
