XBP1 modulates endoplasmic reticulum and mitochondria crosstalk via regulating NLRP3 in renal ischemia/reperfusion injury
Abstract The functional status of mitochondria and the endoplasmic reticulum are central to renal ischemia/reperfusion injury (IRI). X-box binding protein 1 (XBP1) is an important transcription factor in endoplasmic reticulum stress. NLR family pyrin domain containing-3 (NLRP3) inflammatory bodies a...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-02-01
|
| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-023-01360-x |
| _version_ | 1797865521046093824 |
|---|---|
| author | Haiqiang Ni Zhiyu Ou Yuchen Wang Yanna Liu Kailun Sun Ji Zhang Jiasi Zhang Wenfeng Deng Wenli Zeng Renfei Xia Jian Xu Nianqiao Gong Yun Miao |
| author_facet | Haiqiang Ni Zhiyu Ou Yuchen Wang Yanna Liu Kailun Sun Ji Zhang Jiasi Zhang Wenfeng Deng Wenli Zeng Renfei Xia Jian Xu Nianqiao Gong Yun Miao |
| author_sort | Haiqiang Ni |
| collection | DOAJ |
| description | Abstract The functional status of mitochondria and the endoplasmic reticulum are central to renal ischemia/reperfusion injury (IRI). X-box binding protein 1 (XBP1) is an important transcription factor in endoplasmic reticulum stress. NLR family pyrin domain containing-3 (NLRP3) inflammatory bodies are closely related to renal IRI. In vivo and in vitro, we examined the molecular mechanisms and functions of XBP1-NLRP3 signaling in renal IRI, which influences ER-mitochondrial crosstalk. In this study, mice were subjected to 45 min of unilateral renal warm ischemia, the other kidney resected, and reperfusion was performed for 24 h in vivo. In vitro, murine renal tubular epithelial cells (TCMK-1) were exposed to hypoxia for 24 h and reoxygenation for 2 h. Tissue or cell damage was evaluated by measuring blood urea nitrogen and creatinine levels, histological staining, flow cytometry, terminal deoxynucleotidyl transferase-mediated nick-end labeling, diethylene glycol staining, and transmission electron microscopy (TEM). Western blotting, immunofluorescence staining, and ELISA were used to analyze protein expression. Whether XBP1 regulates the NLRP3 promoter was evaluated using a luciferase reporter assay. Kidney damage was reduced with decreasing blood urea nitrogen, creatinine, interleukin-1β, and interleukin-18 levels. XBP1 deficiency reduced tissue damage and cell apoptosis, protecting the mitochondria. Disruption of XBP1 was associated with reduced NLRP3 and cleaved caspase-1 levels and markedly improved survival. In vitro in TCMK-1 cells, XBP1 interference inhibited caspase-1-dependent mitochondrial damage and reduced the production of mitochondrial reactive oxygen species. The luciferase assay showed that spliced XBP1 isoforms enhanced the activity of the NLRP3 promoter. These findings reveal that XBP1 downregulation suppresses the expression of NLRP3, a potential regulator of endoplasmic reticulum mitochondrial crosstalk in nephritic injury and a potential therapeutic target in XBP1-mediated aseptic nephritis. |
| first_indexed | 2024-04-09T23:10:31Z |
| format | Article |
| id | doaj.art-22b599f066d34c479801afcfdf95d3f0 |
| institution | Directory Open Access Journal |
| issn | 2058-7716 |
| language | English |
| last_indexed | 2024-04-09T23:10:31Z |
| publishDate | 2023-02-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj.art-22b599f066d34c479801afcfdf95d3f02023-03-22T10:25:40ZengNature Publishing GroupCell Death Discovery2058-77162023-02-019111210.1038/s41420-023-01360-xXBP1 modulates endoplasmic reticulum and mitochondria crosstalk via regulating NLRP3 in renal ischemia/reperfusion injuryHaiqiang Ni0Zhiyu Ou1Yuchen Wang2Yanna Liu3Kailun Sun4Ji Zhang5Jiasi Zhang6Wenfeng Deng7Wenli Zeng8Renfei Xia9Jian Xu10Nianqiao Gong11Yun Miao12Department of Transplantation, Nanfang Hospital, Southern Medical UniversityDepartment of Transplantation, Nanfang Hospital, Southern Medical UniversityDepartment of Transplantation, Nanfang Hospital, Southern Medical UniversityDepartment of Gastroenterology and Hepatology, Beijing Youan Hospital, Capital Medical UniversityInstitute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyInstitute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyInstitute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Transplantation, Nanfang Hospital, Southern Medical UniversityDepartment of Transplantation, Nanfang Hospital, Southern Medical UniversityDepartment of Transplantation, Nanfang Hospital, Southern Medical UniversityDepartment of Transplantation, Nanfang Hospital, Southern Medical UniversityInstitute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Transplantation, Nanfang Hospital, Southern Medical UniversityAbstract The functional status of mitochondria and the endoplasmic reticulum are central to renal ischemia/reperfusion injury (IRI). X-box binding protein 1 (XBP1) is an important transcription factor in endoplasmic reticulum stress. NLR family pyrin domain containing-3 (NLRP3) inflammatory bodies are closely related to renal IRI. In vivo and in vitro, we examined the molecular mechanisms and functions of XBP1-NLRP3 signaling in renal IRI, which influences ER-mitochondrial crosstalk. In this study, mice were subjected to 45 min of unilateral renal warm ischemia, the other kidney resected, and reperfusion was performed for 24 h in vivo. In vitro, murine renal tubular epithelial cells (TCMK-1) were exposed to hypoxia for 24 h and reoxygenation for 2 h. Tissue or cell damage was evaluated by measuring blood urea nitrogen and creatinine levels, histological staining, flow cytometry, terminal deoxynucleotidyl transferase-mediated nick-end labeling, diethylene glycol staining, and transmission electron microscopy (TEM). Western blotting, immunofluorescence staining, and ELISA were used to analyze protein expression. Whether XBP1 regulates the NLRP3 promoter was evaluated using a luciferase reporter assay. Kidney damage was reduced with decreasing blood urea nitrogen, creatinine, interleukin-1β, and interleukin-18 levels. XBP1 deficiency reduced tissue damage and cell apoptosis, protecting the mitochondria. Disruption of XBP1 was associated with reduced NLRP3 and cleaved caspase-1 levels and markedly improved survival. In vitro in TCMK-1 cells, XBP1 interference inhibited caspase-1-dependent mitochondrial damage and reduced the production of mitochondrial reactive oxygen species. The luciferase assay showed that spliced XBP1 isoforms enhanced the activity of the NLRP3 promoter. These findings reveal that XBP1 downregulation suppresses the expression of NLRP3, a potential regulator of endoplasmic reticulum mitochondrial crosstalk in nephritic injury and a potential therapeutic target in XBP1-mediated aseptic nephritis.https://doi.org/10.1038/s41420-023-01360-x |
| spellingShingle | Haiqiang Ni Zhiyu Ou Yuchen Wang Yanna Liu Kailun Sun Ji Zhang Jiasi Zhang Wenfeng Deng Wenli Zeng Renfei Xia Jian Xu Nianqiao Gong Yun Miao XBP1 modulates endoplasmic reticulum and mitochondria crosstalk via regulating NLRP3 in renal ischemia/reperfusion injury Cell Death Discovery |
| title | XBP1 modulates endoplasmic reticulum and mitochondria crosstalk via regulating NLRP3 in renal ischemia/reperfusion injury |
| title_full | XBP1 modulates endoplasmic reticulum and mitochondria crosstalk via regulating NLRP3 in renal ischemia/reperfusion injury |
| title_fullStr | XBP1 modulates endoplasmic reticulum and mitochondria crosstalk via regulating NLRP3 in renal ischemia/reperfusion injury |
| title_full_unstemmed | XBP1 modulates endoplasmic reticulum and mitochondria crosstalk via regulating NLRP3 in renal ischemia/reperfusion injury |
| title_short | XBP1 modulates endoplasmic reticulum and mitochondria crosstalk via regulating NLRP3 in renal ischemia/reperfusion injury |
| title_sort | xbp1 modulates endoplasmic reticulum and mitochondria crosstalk via regulating nlrp3 in renal ischemia reperfusion injury |
| url | https://doi.org/10.1038/s41420-023-01360-x |
| work_keys_str_mv | AT haiqiangni xbp1modulatesendoplasmicreticulumandmitochondriacrosstalkviaregulatingnlrp3inrenalischemiareperfusioninjury AT zhiyuou xbp1modulatesendoplasmicreticulumandmitochondriacrosstalkviaregulatingnlrp3inrenalischemiareperfusioninjury AT yuchenwang xbp1modulatesendoplasmicreticulumandmitochondriacrosstalkviaregulatingnlrp3inrenalischemiareperfusioninjury AT yannaliu xbp1modulatesendoplasmicreticulumandmitochondriacrosstalkviaregulatingnlrp3inrenalischemiareperfusioninjury AT kailunsun xbp1modulatesendoplasmicreticulumandmitochondriacrosstalkviaregulatingnlrp3inrenalischemiareperfusioninjury AT jizhang xbp1modulatesendoplasmicreticulumandmitochondriacrosstalkviaregulatingnlrp3inrenalischemiareperfusioninjury AT jiasizhang xbp1modulatesendoplasmicreticulumandmitochondriacrosstalkviaregulatingnlrp3inrenalischemiareperfusioninjury AT wenfengdeng xbp1modulatesendoplasmicreticulumandmitochondriacrosstalkviaregulatingnlrp3inrenalischemiareperfusioninjury AT wenlizeng xbp1modulatesendoplasmicreticulumandmitochondriacrosstalkviaregulatingnlrp3inrenalischemiareperfusioninjury AT renfeixia xbp1modulatesendoplasmicreticulumandmitochondriacrosstalkviaregulatingnlrp3inrenalischemiareperfusioninjury AT jianxu xbp1modulatesendoplasmicreticulumandmitochondriacrosstalkviaregulatingnlrp3inrenalischemiareperfusioninjury AT nianqiaogong xbp1modulatesendoplasmicreticulumandmitochondriacrosstalkviaregulatingnlrp3inrenalischemiareperfusioninjury AT yunmiao xbp1modulatesendoplasmicreticulumandmitochondriacrosstalkviaregulatingnlrp3inrenalischemiareperfusioninjury |