Department of Nephrology, Kidney Hospital, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
Department of Nephrology, Kidney Hospital, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
Biochem Biophys Res Commun. 2019 Sep 3;516(4):1137-1144. doi: 10.1016/j.bbrc.2019.06.157. Epub 2019 Jul 6.
Hyperglycemia-induced podocyte injury plays a vital role in the development of diabetic nephropathy. Sulfiredoxin-1 (Srxn1) is emerging as a cytoprotective protein that protects from various insults in a wide range of cell types. However, whether Srxn1 is involved in regulating hyperglycemia-induced podocyte injury and participates in diabetic nephropathy remains unknown. In the present study, we aimed to explore the potential role of Srxn1 in regulating high glucose (HG)-induced apoptosis and oxidative stress of podocytes in vitro. Results demonstrated that Srxn1 was induced in HG-stimulated podocytes. The depletion of Srxn1 by Srxn1 siRNA-mediated gene silencing significantly exacerbated HG-induced apoptosis and the production of reactive oxygen species (ROS), while Srxn1 overexpression attenuated HG-induced apoptosis and ROS production. In-depth molecular mechanism research revealed that Srxn1 overexpression promoted the nuclear expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and reinforced antioxidant response element (ARE)-mediated transcription activity. Moreover, results confirmed that Srxn1 increased the activation of Nrf2/ARE signaling associated with inactivating glycogen synthase kinase (GSK)-3β. Notably, the inhibition of GSK-3β significantly reversed Srxn1 silencing-induced adverse effects in HG-treated cells, while the knockdown of Nrf2 abrogated the Srxn1-mediated protective effect against HG-induced podocyte injury. Taken together, our results demonstrated that Srxn1 protects podocytes from HG-induced injury by promoting the activation of Nrf2/ARE signaling associated with inactivating GSK-3β, indicating a potential role of Srxn1 in diabetic nephropathy. Our study suggests that Srxn1 may serve as a potential target for kidney protection.
高血糖诱导的足细胞损伤在糖尿病肾病的发生发展中起着至关重要的作用。硫氧还蛋白-1（Srxn1）作为一种细胞保护蛋白，在多种细胞类型中对各种损伤具有保护作用。然而，Srxn1 是否参与调节高血糖诱导的足细胞损伤并参与糖尿病肾病尚不清楚。本研究旨在探讨 Srxn1 在体外调节高糖（HG）诱导的足细胞凋亡和氧化应激中的潜在作用。结果表明，Srxn1 在 HG 刺激的足细胞中被诱导。Srxn1 siRNA 介导的基因沉默耗尽 Srxn1 显著加剧了 HG 诱导的凋亡和活性氧（ROS）的产生，而 Srxn1 过表达则减弱了 HG 诱导的凋亡和 ROS 的产生。深入的分子机制研究表明，Srxn1 过表达促进了核因子（红细胞衍生 2）样 2（Nrf2）的核表达，并增强了抗氧化反应元件（ARE）介导的转录活性。此外，结果证实 Srxn1 增加了与糖原合酶激酶（GSK）-3β失活相关的 Nrf2/ARE 信号的激活。值得注意的是，GSK-3β 的抑制显著逆转了 Srxn1 沉默在 HG 处理细胞中引起的不良影响，而 Nrf2 的敲低则消除了 Srxn1 对 HG 诱导的足细胞损伤的保护作用。综上所述，我们的研究结果表明，Srxn1 通过促进与失活 GSK-3β 相关的 Nrf2/ARE 信号的激活来保护足细胞免受 HG 诱导的损伤，表明 Srxn1 在糖尿病肾病中可能发挥作用。我们的研究表明，Srxn1 可能是肾脏保护的潜在靶点。
