Matrine-induced nephrotoxicity via GSK-3β/nrf2-mediated mitochondria-dependent apoptosis

Matrine (MT), an ingredient extracted from the Chinese herb Sophora flavescens, can result in nephrotoxicity because of long-term exposure. However, the underlying mechanism by which MT leads to kidney injury remains unclear. This study aimed to investigate the roles of oxidative stress and mitochondria in MT-induced kidney toxicity both in vitro and in vivo.Mice were exposed to MT for 20 days, and NRK-52E cells were exposed to MT with or without LiCl (a GSK-3β inhibitor), tert-Butylhydroquinone (t-BHQ, an Nrf2 activator), or small interfering RNA.The results showed that MT caused nephrotoxicity accompanied by an increase in reactive oxygen species (ROS) accumulation and mitochondrial dysfunction. Meanwhile, MT significantly upregulated glycogen synthase kinase-3β (GSK-3β) activity, released cytochrome c (Cyt C) and cleaved caspase-3, decreased the activity of nuclear factor-erythroid 2-related Factor 2 (Nrf2), and reduced the expression of heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO-1), which led to the inactivation of antioxidant enzymes and the activation of apoptosis. In addition, GSK-3β inhibition by LiCl or small interfering RNA pretreatment or Nrf2 activation by t-BHQ pretreatment attenuated the toxic effects of MT in NRK-52E cells.Taken together, these results revealed that MT-induced apoptosis triggered kidney toxicity and that GSK-3β or Nrf2 might serve as a promising nephroprotective target for MT-induced kidney injury.