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.
Highlights
Diabetic nephropathy (DN) is a diabetes-induced microvascular complication that leads to end-stage renal disease (ESRD)[1], with the progressive albuminuria as the hallmark due to compromised glomerular filtration barrier (GFB)[2]
Both blood urea nitrogen (BUN) and serum creatinine levels were markedly elevated in diabetic nephropathy (DN)-vehicle group relative to NC-vehicle group, which were significantly reduced by Astragaloside IV (AS-IV) treatment in a dose-dependent manner (Fig. 1B,C)
The protective effect of AS-IV was associated with Endoplasmic reticulum (ER) stress attenuation via sarcoendoplasmic reticulum Ca2+ ATPase 2b (SERCA2b) restoration and autophagy enhancement through AMPKα activation, which subsequently protected podocytes from hyperglycemia or high glucose (HG)-induced apoptosis
Summary
Diabetic nephropathy (DN) is a diabetes-induced microvascular complication that leads to end-stage renal disease (ESRD)[1], with the progressive albuminuria as the hallmark due to compromised glomerular filtration barrier (GFB)[2]. Autophagy deficiency in podocytes exacerbates proteinuria in DN24 These studies highlight the significance of constitutive and induced autophagy in protecting against podocyte injury and proteinuria. The mammalian target of rapamycin (mTOR) signaling has been reported to negatively regulate autophagy induction[16, 25], while AMP-activated protein kinase (AMPK) activation may inhibit mTOR signaling pathway and promote autophagy in many kinds of cells[26]. Though AS-IV has been reported to protect podocytes and prevent DN development by inhibiting ER stress in type 1 diabetes, the underlying mechanism for AS-IV-reduced ER stress warrants further investigation. This work aims to explore the mechanism by which AS-IV attenuates ER stress and the role of autophagy in the action of AS-IV in STZ-induced type 1 diabetic mice in vivo and in high glucose (HG)-cultured podocytes in vitro
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