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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Abstract

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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Guo, H., Wang, Y., Zhang, X., Zang, Y., Zhang, Y., Wang, L., … Peng, W. (2017). Astragaloside IV protects against podocyte injury via SERCA2-dependent ER stress reduction and AMPKα-regulated autophagy induction in streptozotocin-induced diabetic nephropathy. Scientific Reports, 7(1). https://doi.org/10.1038/s41598-017-07061-7

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