Department of Molecular Biology, Institute for Biological Research "Siniša Stanković", National Institute of Republic of Serbia, University of Belgrade, Belgrade, Serbia.
Department of Immunology, Institute for Biological Research "Siniša Stanković", National Institute of Republic of Serbia, University of Belgrade, Belgrade, Belgrade, Serbia.
Oxid Med Cell Longev. 2022 Mar 14;2022:3873420. doi: 10.1155/2022/3873420. eCollection 2022.
The main pathological hallmark of diabetes is the loss of functional -cells. Among several types of -cell death in diabetes, the involvement of ferroptosis remains elusive. Therefore, we investigated the potential of diabetes-mimicking factors: high glucose (HG), proinflammatory cytokines, hydrogen peroxide (HO), or diabetogenic agent streptozotocin (STZ) to induce ferroptosis of -cells . Furthermore, we tested the contribution of ferroptosis to injury of pancreatic islets in an STZ-induced diabetic model. All treatments increased loss of Rin-5F cells along with the accumulation of reactive oxygen species, lipid peroxides and iron, inactivation of NF-E2-related factor 2 (Nrf2), and decrease in glutathione peroxidase 4 expression and mitochondrial membrane potential (MMP). Ferrostatin 1 (Fer-1), ferroptosis inhibitor, diminished the above-stated effects and rescued cells from death in case of HG, STZ, and HO treatments, while failed to increase MMP and to attenuate cell death after the cytokines' treatment. Moreover, Fer-1 protected pancreatic islets from STZ-induced injury in diabetic model, since it decreased infiltration of macrophages and accumulation of lipid peroxides and increased the population of insulin-positive cells. Such results revealed differences between diabetogenic stimuli in determining the destiny of -cells, emerging HG, HO, and STZ, but not cytokines, as contributing factors to ferroptosis and shed new light on an antidiabetic strategy based on Nrf2 activation. Thus, targeting ferroptosis in diabetes might be a promising new approach for preservation of the -cell population. Our results obtained from study strongly justify this approach.
糖尿病的主要病理学特征是功能性细胞的丧失。在糖尿病的几种细胞死亡类型中，铁死亡的参与仍然难以捉摸。因此，我们研究了糖尿病模拟因素的潜力：高葡萄糖（HG）、促炎细胞因子、过氧化氢（HO）或致糖尿病剂链脲佐菌素（STZ）是否能诱导β细胞发生铁死亡。此外，我们测试了铁死亡在 STZ 诱导的糖尿病模型中对胰岛损伤的贡献。所有这些治疗方法都增加了 Rin-5F 细胞的丢失，同时伴随着活性氧、脂质过氧化物和铁的积累、核因子 E2 相关因子 2（Nrf2）失活以及谷胱甘肽过氧化物酶 4 表达和线粒体膜电位（MMP）的下降。铁死亡抑制剂 Fer-1 减弱了上述作用，并在 HG、STZ 和 HO 治疗中挽救了细胞免于死亡，而在细胞因子治疗后，它无法增加 MMP 并减轻细胞死亡。此外，Fer-1 还保护胰岛免受糖尿病模型中 STZ 诱导的损伤，因为它减少了巨噬细胞的浸润和脂质过氧化物的积累，并增加了胰岛素阳性细胞的数量。这些结果揭示了不同的致糖尿病刺激在决定β细胞命运方面的差异，出现 HG、HO 和 STZ，但不是细胞因子，作为铁死亡的促成因素，并为基于 Nrf2 激活的抗糖尿病策略提供了新的思路。因此，针对糖尿病的铁死亡可能是保护β细胞群体的一种有前途的新方法。我们从这项研究中获得的结果强烈证明了这一方法的合理性。
