Glutathione prevents high glucose-induced pancreatic fibrosis by suppressing pancreatic stellate cell activation via the ROS/TGFβ/SMAD pathway |
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| Authors: | Jitai Zhang Juan Bai Qian Zhou Yuxin Hu Qian Wang Lanting Yang Huamin Chen Hui An Chuanzan Zhou Yongyu Wang Xiufang Chen Ming Li |
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| Affiliation: | 1.Cardiac Regeneration Research Institute, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China ;2.Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China ;3.Department of Anesthesia and Critical Care, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China ;4.The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China |
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| Abstract: | 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.Subject terms: Pre-diabetes, Pre-diabetes |
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