Abstract
Salvianolic acid A (SAA) is a bioactive polyphenol extracted from Salviae miltiorrhizae Bunge, which possesses a variety of pharmacological activities. In our previous study, we have demonstrated that SAA effectively attenuates kidney injury and inflammation in an established animal model of 5/6 nephrectomized (5/6Nx) rats. However, there has been limited research regarding the antioxidative effects of SAA on chronic kidney disease (CKD). Here, we examined the antioxidative effects and underlying mechanisms of SAA in 5/6Nx rats. The rats were injected with SAA (2.5, 5, and 10 mg·kg−1·d−1, ip) for 28 days. Biochemical, flow cytometry, and Western blot analyses showed that SAA significantly increased the activities of total superoxide dismutase (T-SOD), glutathione peroxidase (GPx), and catalase (CAT) and lowered the levels of malondialdehyde (MDA), reactive oxygen species (ROS), and NADPH oxidase 4 (NOX-4) in a dose-dependent manner in 5/6Nx rats and in H2O2-induced HK-2 cells in vitro. Moreover, SAA enhanced the activation of the protein kinase B/glycogen synthase kinase-3β/nuclear factor-erythroid-2-related factor 2 (Akt/GSK-3β/Nrf2) signaling pathway in a dose-dependent manner and subsequently increased the expression of heme oxygenase-1 (HO-1) in the kidney of 5/6Nx rats, which were consistent with those obtained in H2O2-induced HK-2 cells in vitro shown by Western blot analysis. Furthermore, SAA significantly increased the expression of intranuclear Nrf2 and HO-1 proteins compared to HK-2 cells stimulated by LPS on the one hand, which can be enhanced by QNZ to some extent; on the other hand, SAA significantly lowered the expression of p-NF-κB p65 and ICAM-1 proteins compared to HK-2 cells stimulated by H2O2, which can be abrogated by ML385 to some extent. In conclusion, our results demonstrated that SAA effectively protects the kidney against oxidative stress in 5/6Nx rats. One of the pivotal mechanisms for the protective effects of SAA on kidney injury was mainly related with its antioxidative roles by activating the Akt/GSK-3β/Nrf2 signaling pathway and inhibiting the NF-κB signaling pathway.
Highlights
Chronic kidney disease (CKD) has high morbidity and mortality and has become a serious public health concern worldwide [1,2,3]
The results show that the levels of MDA and reactive oxygen species (ROS) were significantly increased in 5/6Nx rats compared to the control group, while the activities of total superoxide dismutase (T-superoxide dismutase (SOD)), glutathione peroxidase (GPx), and CAT were all decreased, which suggests that oxidative stress was grievous in this model (Figure 1)
Administration of Salvianolic acid A (SAA) significantly increased the activities of T-SOD, GPx, and CAT compared to the untreated 5/6Nx group and lowered the levels of MDA and ROS in a dose-dependent manner (Figure 1) suggesting that SAA plays a key role in this model
Summary
Chronic kidney disease (CKD) has high morbidity and mortality and has become a serious public health concern worldwide [1,2,3]. According to a systematic analysis for the 2015 Global Burden of Disease Study, the mortality of CKD increased by about 30% and attributable mortality and disabilityadjusted life-years significantly increased between 2005 and 2015, which was due to low glomerular filtration rates [4]. Two important features of CKD are oxidative stress and inflammation, which are inseparably linked and play key roles in driving the development and progression of CKD and other complications [5]. Inhibiting oxidative stress may delay the progression of CKD. 5/6 nephrectomized (5/6Nx) rats were used to model chronic kidney disease and have frequently been used to study the progression of CKD [7,8,9]. HK-2 cells stimulated in vitro with H2O2 were used to identify antioxidative effects in the kidney [11,12,13]
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