Abstract
Astragaloside II (AS II), a novel saponin purified from Astragalus membranes, has been reported to modulate the immune response, repair tissue injury, and prevent inflammatory response. However, the protective effects of AS II on podocyte injury in diabetic nephropathy (DN) have not been investigated yet. In this study, we aimed to investigate the beneficial effects of AS II on podocyte injury and mitochondrial dysfunction in DN. Diabetes was induced with streptozotocin (STZ) by intraperitoneal injection at 55 mg/kg in rats. Diabetic rats were randomly divided into four groups, namely, diabetic rats and diabetic rats treated with losartan (10 mg·kg−1·d−1) or AS II (3.2 and 6.4 mg·kg−1·d−1) for 9 weeks. Normal Sprague-Dawley rats were chosen as nondiabetic control group. Urinary albumin/creatinine ratio (ACR), biochemical parameters, renal histopathology and podocyte apoptosis, and morphological changes were evaluated. Expressions of mitochondrial dynamics-related and autophagy-related proteins, such as Mfn2, Fis1, P62, and LC3, as well as Nrf2, Keap1, PINK1, and Parkin, were examined by immunohistochemistry, western blot, and real-time PCR, respectively. Our results indicated that AS II ameliorated albuminuria, renal histopathology, and podocyte foot process effacement and podocyte apoptosis in diabetic rats. AS II also partially restored the renal expression of mitochondrial dynamics-related and autophagy-related proteins, including Mfn2, Fis1, P62, and LC3. AS II also increased the expression of PINK1 and Parkin associated with mitophagy in diabetic rats. Moreover, AS II facilitated antioxidative stress ability via increasing Nrf2 expression and decreasing Keap1 protein level. These results suggested that AS II ameliorated podocyte injury and mitochondrial dysfunction in diabetic rats partly through regulation of Nrf2 and PINK1 pathway. These important findings might provide an innovative therapeutic strategy for the treatment of DN.
Highlights
Diabetic nephrology (DN) is one of the most common causes of end-stage renal disease (ESRD) (Lindblom et al, 2015; Papadopoulou-Marketou et al, 2017)
The diabetic rats were randomly divided into four groups (n 7/each group): 1) STZ-induced diabetic rats (STZ), received an equal volume of olive oil; 2) diabetic rats treated with losartan at 10 mg·kg−1·d−1; 3) diabetic rats treated with low-concentration of Astragaloside II (AS II) at 3.2 mg·kg−1·d−1 (ASIIL); 4) diabetic treated with highconcentration of AS II at 6.4 mg·kg−1·d−1 (ASIIH)
No significant difference in the level of GLU was observed between AS II and losartan treatment groups, which indicated that AS II had no direct effect on the levels of blood glucose (Figure 1C)
Summary
Diabetic nephrology (DN) is one of the most common causes of end-stage renal disease (ESRD) (Lindblom et al, 2015; Papadopoulou-Marketou et al, 2017). Terminal differentiated cells that play essential roles in maintaining glomerular filtration barrier integrity (Liu et al, 2017). Podocyte apoptosis played critical roles in the progression of DN (Susztak et al, 2006). Excessive mitochondrial fission is a key mediator that produces a massive amount of reactive oxygen species (ROS) and apoptogenic proteins (e.g., caspase3), eventually activating the death pathway of mitochondria (Xiao et al, 2017). These studies suggest that the perturbation of mitochondrial dynamics is likely associated with renal function deterioration and podocyte injury
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