Astragaloside IV attenuates high glucose‐induced NF‐κB‐mediated inflammation through activation of PI3K/AKT‐ERK‐dependent Nrf2/ARE signaling pathway in glomerular mesangial cells

Abstract

AbstractInflammation is a key contributor to diabetic kidney disease pathogenesis, including reactive oxidation stress (ROS)‐mediated nuclear factor‐κB (NF‐κB) signaling pathway. In this study, we examined the effect of Astragaloside IV (AS‐IV) on anti‐inflammatory and anti‐oxidative properties under high glucose (HG) condition and the potential mechanism in glomerular mesangial cells (GMCs). We showed that AS‐IV concentration‐dependently reduced GMCs proliferation, restrained ROS release and hydrogen peroxide content, and suppressed pro‐inflammatory cytokines as well as pro‐fibrotic factors expression, which were associated with the inhibition of NF‐κB and nuclear factor‐erythroid 2‐related factor 2 (Nrf2) signaling activation. Accordingly, both NF‐κB overexpression by using RNA plasmid and Nrf2 gene silencing by using RNA interference weakened the ability of AS‐IV to ameliorate HG‐induced oxidative stress, inflammation, and cell proliferation. Furthermore, phosphatidylinositide 3‐kinases (PI3K)/serine/threonine protein kinase (Akt) and extracellular regulated protein kinases (ERK) signaling pathway regulated the process of AS‐IV‐induced Nrf2 activation and antioxidant capacity, which evidenced by using PI3K inhibitor LY294002 or ERK inhibitor PD98059 that largely abolished the AS‐IV efficacy. Taken together, these results indicated that AS‐IV protected against HG‐induced GMCs damage by inhibiting ROS/NF‐kB‐induced increases of inflammatory cytokines, fibrosis biomarkers, and cell proliferation via up‐regulation of Nrf2‐dependent antioxidant enzyme expression, which were mediated by PI3K/Akt and ERK signaling pathway activation.