Salvianolic Acid A Protects the Kidney against Oxidative Stress by Activating the Akt/GSK-3 β/Nrf2 Signaling Pathway and Inhibiting the NF- κ B Signaling Pathway in 5/6 Nephrectomized Rats

Oxid Med Cell Longev. 2019 Mar 18:2019:2853534. doi: 10.1155/2019/2853534. eCollection 2019.

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.

MeSH terms

  • Animals
  • Caffeic Acids / pharmacology*
  • Cell Line
  • Cell Survival / drug effects
  • Glycogen Synthase Kinase 3 beta / metabolism
  • Hydrogen Peroxide / toxicity
  • Kidney / pathology*
  • Lactates / pharmacology*
  • Lipopolysaccharides
  • Male
  • Models, Biological
  • NF-E2-Related Factor 2 / metabolism*
  • NF-kappa B / metabolism*
  • Nephrectomy*
  • Oxidative Stress / drug effects*
  • Protective Agents / pharmacology*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects*

Substances

  • Caffeic Acids
  • Lactates
  • Lipopolysaccharides
  • NF-E2-Related Factor 2
  • NF-kappa B
  • Protective Agents
  • salvianolic acid A
  • Hydrogen Peroxide
  • Glycogen Synthase Kinase 3 beta
  • Proto-Oncogene Proteins c-akt