Cardiac Regeneration Research Institute, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China.
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China.
Cell Death Dis. 2022 May 6;13(5):440. doi: 10.1038/s41419-022-04894-7.
The activation of pancreatic stellate cells (PSCs) is the key mechanism of pancreatic fibrosis, which can lead to β-cell failure. Oxidative stress is an important risk factor for PSC activation. There is no direct evidence proving if administration of glutathione can inhibit fibrosis and β-cell failure. To explore the role of glutathione in pancreatic fibrosis and β-cell failure induced by hyperglycaemia, we established a rat model of pancreatic fibrosis and β-cell failure. The model was founded through long-term oscillating glucose (LOsG) intake and the setup of a sham group and a glutathione intervention group. In vitro, rat PSCs were treated with low glucose, high glucose, or high glucose plus glutathione to explore the mechanism of high glucose-induced PSC activation and the downstream effects of glutathione. Compared with sham rats, LOsG-treated rats had higher reactive oxygen species (ROS) levels in peripheral leukocytes and pancreatic tissue while TGFβ signalling was upregulated. In addition, as the number of PSCs and pancreatic fibrosis increased, β-cell function was significantly impaired. Glutathione evidently inhibited the upregulation of TGFβ signalling and several unfavourable outcomes caused by LOsG. In vitro treatment of high glucose for 72 h resulted in higher ROS accumulation and potentiated TGFβ pathway activation in PSCs. PSCs showed myofibroblast phenotype transformation with upregulation of α-SMA expression and increased cell proliferation and migration. Treatment with either glutathione or TGFβ pathway inhibitors alleviated these changes. Together, our findings suggest that glutathione can inhibit PSC activation-induced pancreatic fibrosis via blocking ROS/TGFβ/SMAD signalling in vivo and in vitro.
胰腺星状细胞（PSCs）的激活是胰腺纤维化的关键机制，可导致β细胞衰竭。氧化应激是 PSC 激活的一个重要危险因素。目前尚无直接证据证明谷胱甘肽的给药是否能抑制纤维化和β细胞衰竭。为了探讨谷胱甘肽在高血糖诱导的胰腺纤维化和β细胞衰竭中的作用，我们建立了一个胰腺纤维化和β细胞衰竭的大鼠模型。该模型通过长期波动葡萄糖（LOsG）摄入以及设立假手术组和谷胱甘肽干预组来建立。在体外，用低葡萄糖、高葡萄糖或高葡萄糖加谷胱甘肽处理大鼠 PSCs，以探讨高葡萄糖诱导 PSC 激活的机制以及谷胱甘肽的下游效应。与假手术大鼠相比，LOsG 处理大鼠外周白细胞和胰腺组织中的活性氧（ROS）水平升高，TGFβ 信号转导上调。此外，随着 PSCs 数量和胰腺纤维化的增加，β细胞功能明显受损。谷胱甘肽明显抑制了 LOsG 引起的 TGFβ 信号转导上调和几种不良后果。体外高葡萄糖处理 72 h 导致 ROS 积累增加，并增强 PSCs 中 TGFβ 通路的激活。PSCs 表现出肌成纤维细胞表型转化，α-SMA 表达上调，细胞增殖和迁移增加。用谷胱甘肽或 TGFβ 通路抑制剂处理可缓解这些变化。总之，我们的研究结果表明，谷胱甘肽可以通过在体内和体外阻断 ROS/TGFβ/SMAD 信号通路来抑制 PSC 激活诱导的胰腺纤维化。
