Glutathione prevents high glucose-induced pancreatic fibrosis by suppressing pancreatic stellate cell activation via the ROS/TGFβ/SMAD pathway
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-...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2022-05-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-04894-7 |
| _version_ | 1811305901626228736 |
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| author | Jitai Zhang Juan Bai Qian Zhou Yuxin Hu Qian Wang Lanting Yang Huamin Chen Hui An Chuanzan Zhou Yongyu Wang Xiufang Chen Ming Li |
| author_facet | Jitai Zhang Juan Bai Qian Zhou Yuxin Hu Qian Wang Lanting Yang Huamin Chen Hui An Chuanzan Zhou Yongyu Wang Xiufang Chen Ming Li |
| author_sort | Jitai Zhang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T08:34:43Z |
| format | Article |
| id | doaj.art-a18087588ec444fba8aa49e3191428c7 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-13T08:34:43Z |
| publishDate | 2022-05-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-a18087588ec444fba8aa49e3191428c72022-12-22T02:54:09ZengNature Publishing GroupCell Death and Disease2041-48892022-05-0113511310.1038/s41419-022-04894-7Glutathione prevents high glucose-induced pancreatic fibrosis by suppressing pancreatic stellate cell activation via the ROS/TGFβ/SMAD pathwayJitai Zhang0Juan Bai1Qian Zhou2Yuxin Hu3Qian Wang4Lanting Yang5Huamin Chen6Hui An7Chuanzan Zhou8Yongyu Wang9Xiufang Chen10Ming Li11Cardiac Regeneration Research Institute, School of Basic Medical Sciences, Wenzhou Medical UniversityDepartment of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Wenzhou Medical UniversityDepartment of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Wenzhou Medical UniversityCardiac Regeneration Research Institute, School of Basic Medical Sciences, Wenzhou Medical UniversityCardiac Regeneration Research Institute, School of Basic Medical Sciences, Wenzhou Medical UniversityCardiac Regeneration Research Institute, School of Basic Medical Sciences, Wenzhou Medical UniversityDepartment of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Wenzhou Medical UniversityCardiac Regeneration Research Institute, School of Basic Medical Sciences, Wenzhou Medical UniversityCardiac Regeneration Research Institute, School of Basic Medical Sciences, Wenzhou Medical UniversityCardiac Regeneration Research Institute, School of Basic Medical Sciences, Wenzhou Medical UniversityDepartment of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Wenzhou Medical UniversityCardiac Regeneration Research Institute, School of Basic Medical Sciences, Wenzhou Medical UniversityAbstract 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.https://doi.org/10.1038/s41419-022-04894-7 |
| spellingShingle | Jitai Zhang Juan Bai Qian Zhou Yuxin Hu Qian Wang Lanting Yang Huamin Chen Hui An Chuanzan Zhou Yongyu Wang Xiufang Chen Ming Li Glutathione prevents high glucose-induced pancreatic fibrosis by suppressing pancreatic stellate cell activation via the ROS/TGFβ/SMAD pathway Cell Death and Disease |
| title | Glutathione prevents high glucose-induced pancreatic fibrosis by suppressing pancreatic stellate cell activation via the ROS/TGFβ/SMAD pathway |
| title_full | Glutathione prevents high glucose-induced pancreatic fibrosis by suppressing pancreatic stellate cell activation via the ROS/TGFβ/SMAD pathway |
| title_fullStr | Glutathione prevents high glucose-induced pancreatic fibrosis by suppressing pancreatic stellate cell activation via the ROS/TGFβ/SMAD pathway |
| title_full_unstemmed | Glutathione prevents high glucose-induced pancreatic fibrosis by suppressing pancreatic stellate cell activation via the ROS/TGFβ/SMAD pathway |
| title_short | Glutathione prevents high glucose-induced pancreatic fibrosis by suppressing pancreatic stellate cell activation via the ROS/TGFβ/SMAD pathway |
| title_sort | glutathione prevents high glucose induced pancreatic fibrosis by suppressing pancreatic stellate cell activation via the ros tgfβ smad pathway |
| url | https://doi.org/10.1038/s41419-022-04894-7 |
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