Impaired immunoproteasomal function exacerbates renal ischemia-reperfusion injury
Oxidative stress caused by reactive oxygen species (ROS) is involved in the pathogenesis of renal ischemia-reperfusion injury (I/R injury), a major cause of acute kidney injury and delayed graft function (DGF). DGF is an early transplant complication that worsens graft prognosis and patient survival...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-12-01
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| Series: | Experimental and Molecular Pathology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0014480024000583 |
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| author | Yasushi Ishii Aya Fukui-Miyazaki Sari Iwasaki Takahiro Tsuji Kiyohiko Hotta Hajime Sasaki Shimpei Nakagawa Takuma Yoshida Eri Murata Koji Taniguchi Nobuo Shinohara Akihiro Ishizu Masanori Kasahara Utano Tomaru |
| author_facet | Yasushi Ishii Aya Fukui-Miyazaki Sari Iwasaki Takahiro Tsuji Kiyohiko Hotta Hajime Sasaki Shimpei Nakagawa Takuma Yoshida Eri Murata Koji Taniguchi Nobuo Shinohara Akihiro Ishizu Masanori Kasahara Utano Tomaru |
| author_sort | Yasushi Ishii |
| collection | DOAJ |
| description | Oxidative stress caused by reactive oxygen species (ROS) is involved in the pathogenesis of renal ischemia-reperfusion injury (I/R injury), a major cause of acute kidney injury and delayed graft function (DGF). DGF is an early transplant complication that worsens graft prognosis and patient survival, but the underlying molecular changes are unclear. The proteasome is a multicatalytic enzyme complex that degrades both normal and damaged proteins, and recent studies have revealed that the immunoproteasome, a specific proteasome isoform whose proteolytic activity enhances the generation of antigenic peptides, plays critical roles in the cellular response against oxidative stress. In this study, we demonstrate the impact of the immunoproteasome in human DGF and in a mouse model of I/R injury. In patients with DGF, the expression of β5i, a specific immunoproteasome subunit, was decreased in vascular endothelial cells. In a mouse model, β5i knockout (KO) exacerbated renal I/R injury. KO mice showed greater inflammation, oxidative stress, and endothelial damage compared with wild-type mice. Impaired immunoproteasomal activity also caused increased cell death, ROS production, and expression of inflammatory factors in mouse renal vascular endothelial cells under conditions of hypoxia and reoxygenation. In conclusion, reduced expression of the immunoproteasomal catalytic subunit β5i exacerbates renal I/R injury in vivo, potentially increasing the risk of DGF. Further research targeting β5i expression in DGF could lead to the development of novel therapeutic strategies and biomarkers. |
| format | Article |
| id | doaj-art-93dea25eecb443caa12f099e7bcd8693 |
| institution | Kabale University |
| issn | 1096-0945 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Experimental and Molecular Pathology |
| spelling | doaj-art-93dea25eecb443caa12f099e7bcd86932024-12-18T08:46:55ZengElsevierExperimental and Molecular Pathology1096-09452024-12-01140104939Impaired immunoproteasomal function exacerbates renal ischemia-reperfusion injuryYasushi Ishii0Aya Fukui-Miyazaki1Sari Iwasaki2Takahiro Tsuji3Kiyohiko Hotta4Hajime Sasaki5Shimpei Nakagawa6Takuma Yoshida7Eri Murata8Koji Taniguchi9Nobuo Shinohara10Akihiro Ishizu11Masanori Kasahara12Utano Tomaru13Department of Pathology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, JapanDepartment of Medical Laboratory Science, Faculty of Health Sciences, Hokkaido University, Sapporo, Hokkaido, JapanDepartment of Pathology, Sapporo City General Hospital, Sapporo, Hokkaido, JapanDepartment of Pathology, Sapporo City General Hospital, Sapporo, Hokkaido, JapanDepartment of Renal and Genitourinary Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, JapanDepartment of Kidney Transplant Surgery, Sapporo City General Hospital, Sapporo, Hokkaido, JapanDepartment of Pathology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, JapanDepartment of Pathology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, JapanDepartment of Pathology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan; Department of Fundamental Nursing, School of Nursing, Faculty of Medicine, Yamagata University, Yamagata, JapanDepartment of Pathology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, JapanDepartment of Renal and Genitourinary Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, JapanDepartment of Medical Laboratory Science, Faculty of Health Sciences, Hokkaido University, Sapporo, Hokkaido, JapanDepartment of Pathology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, JapanDepartment of Pathology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan; Department of Surgical Pathology, Hokkaido University Hospital, Sapporo 060-8648, Japan; Corresponding author at: Department of Surgical Pathology, Hokkaido University Hospital, Sapporo 060-8648, Kita-14 Nishi-5, Kita-ku, Japan.Oxidative stress caused by reactive oxygen species (ROS) is involved in the pathogenesis of renal ischemia-reperfusion injury (I/R injury), a major cause of acute kidney injury and delayed graft function (DGF). DGF is an early transplant complication that worsens graft prognosis and patient survival, but the underlying molecular changes are unclear. The proteasome is a multicatalytic enzyme complex that degrades both normal and damaged proteins, and recent studies have revealed that the immunoproteasome, a specific proteasome isoform whose proteolytic activity enhances the generation of antigenic peptides, plays critical roles in the cellular response against oxidative stress. In this study, we demonstrate the impact of the immunoproteasome in human DGF and in a mouse model of I/R injury. In patients with DGF, the expression of β5i, a specific immunoproteasome subunit, was decreased in vascular endothelial cells. In a mouse model, β5i knockout (KO) exacerbated renal I/R injury. KO mice showed greater inflammation, oxidative stress, and endothelial damage compared with wild-type mice. Impaired immunoproteasomal activity also caused increased cell death, ROS production, and expression of inflammatory factors in mouse renal vascular endothelial cells under conditions of hypoxia and reoxygenation. In conclusion, reduced expression of the immunoproteasomal catalytic subunit β5i exacerbates renal I/R injury in vivo, potentially increasing the risk of DGF. Further research targeting β5i expression in DGF could lead to the development of novel therapeutic strategies and biomarkers.http://www.sciencedirect.com/science/article/pii/S0014480024000583ImmunoproteasomeAcute kidney injuryDelayed graft functionIschemia-reperfusion injuryOxidative stressROS |
| spellingShingle | Yasushi Ishii Aya Fukui-Miyazaki Sari Iwasaki Takahiro Tsuji Kiyohiko Hotta Hajime Sasaki Shimpei Nakagawa Takuma Yoshida Eri Murata Koji Taniguchi Nobuo Shinohara Akihiro Ishizu Masanori Kasahara Utano Tomaru Impaired immunoproteasomal function exacerbates renal ischemia-reperfusion injury Experimental and Molecular Pathology Immunoproteasome Acute kidney injury Delayed graft function Ischemia-reperfusion injury Oxidative stress ROS |
| title | Impaired immunoproteasomal function exacerbates renal ischemia-reperfusion injury |
| title_full | Impaired immunoproteasomal function exacerbates renal ischemia-reperfusion injury |
| title_fullStr | Impaired immunoproteasomal function exacerbates renal ischemia-reperfusion injury |
| title_full_unstemmed | Impaired immunoproteasomal function exacerbates renal ischemia-reperfusion injury |
| title_short | Impaired immunoproteasomal function exacerbates renal ischemia-reperfusion injury |
| title_sort | impaired immunoproteasomal function exacerbates renal ischemia reperfusion injury |
| topic | Immunoproteasome Acute kidney injury Delayed graft function Ischemia-reperfusion injury Oxidative stress ROS |
| url | http://www.sciencedirect.com/science/article/pii/S0014480024000583 |
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