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Matrine-induced nephrotoxicity via GSK-3β/nrf2-mediated mitochondria-dependent apoptosis
Tianyang Wang1, Jian Zhang1, Haokai Wei1
1School of Medicine, Yichun University, 576 XueFu Road, Yuanzhou District, Yichun, 336000, PR China.
Introduction:
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.
Methods:
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.
Results:
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.
Conclusions:
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.
Insights
Matrine causes kidney toxicity through oxidative stress and mitochondrial dysfunction. Inhibiting GSK-3β or activating Nrf2 may protect against this damage.
Area of Science:
- Toxicology
- Mitochondrial Biology
- Cellular Signaling
Background:
- Matrine (MT), derived from Sophora flavescens, is linked to nephrotoxicity from prolonged exposure.
- The precise mechanisms of MT-induced kidney injury are not fully understood.
- This study investigates the roles of oxidative stress and mitochondria in MT toxicity.
Purpose of the Study:
- To elucidate the mechanisms of Matrine-induced kidney toxicity.
- To explore the involvement of oxidative stress and mitochondrial dysfunction.
- To identify potential therapeutic targets for mitigating Matrine nephrotoxicity.
Main Methods:
- In vivo study: Mice exposed to Matrine for 20 days.
- In vitro study: NRK-52E cells treated with Matrine, LiCl (GSK-3β inhibitor), t-BHQ (Nrf2 activator), or siRNA.
- Assessment of reactive oxygen species (ROS), mitochondrial function, apoptosis markers, and key protein expressions.
Main Results:
- Matrine induced nephrotoxicity, increased ROS, and impaired mitochondrial function.
- MT upregulated GSK-3β activity, released cytochrome c, and activated caspase-3.
- MT decreased Nrf2 activity and reduced antioxidant enzyme expression (HO-1, NQO-1), promoting apoptosis.
- GSK-3β inhibition or Nrf2 activation attenuated Matrine's toxic effects.
Conclusions:
- Matrine-induced apoptosis contributes to kidney toxicity.
- GSK-3β and Nrf2 are identified as potential nephroprotective targets against Matrine injury.
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