Exosomes secreted by ATF3/Nrf2-mediated ferroptotic renal tubular epithelial cells promote M1/M2 ratio imbalance inducing renal interstitial fibrosis following ischemia and reperfusion injury
BackgroundSevere renal ischemia and reperfusion injury (IRI) progresses to renal interstitial fibrosis (RIF) with limited therapeutic strategies. Although ferrptosis and macrophage polarization both play important roles in this model, their specific pathogenesis and interactions have not been elucid...
Saved in:
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2025-02-01
|
| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1510500/full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832539887023161344 |
|---|---|
| author | Qiao Tang Jiatao Xie Yifei Wang Chong Dong Chong Dong Qian Sun |
| author_facet | Qiao Tang Jiatao Xie Yifei Wang Chong Dong Chong Dong Qian Sun |
| author_sort | Qiao Tang |
| collection | DOAJ |
| description | BackgroundSevere renal ischemia and reperfusion injury (IRI) progresses to renal interstitial fibrosis (RIF) with limited therapeutic strategies. Although ferrptosis and macrophage polarization both play important roles in this model, their specific pathogenesis and interactions have not been elucidated. Therefore, we aimed to explore the mechanisms by which ferrotosis occurs in renal tubular epithelial cells (RTECs) and ferroptotic cell-derived exosomes induce macrophage polarization in IRI-related RIF model.MethodsIn vivo, C57BL/6J mice were randomly divided into four groups: sham group, ischemia and reperfusion (IR) group, IR + Ferrostatin-1 (Fer-1) group, and IR +ATF3 knockdown (ATFKD) group. In vitro, RTECs were divided into control (CON) group, hypoxia/reoxygenation (HR) group, HR +Fer-1 group, HR + siRNA-ATF3 (siATF3) group.ResultCompared with the sham group, the IR group showed more severe kidney injury in HE staining, more collagen fibers in Masson staining, and higher α-SMA expression levels in immunohistochemistry. Total iron and MDA content increased while GSH content decreased. The IR group had more significant mitochondrial damage and higher PTGS2 and TFRC mRNA levels than those in the sham group. Compared with the IR group, the above indexes were all alleviated in the IR+Fer-1 or IR+ATF3KD groups. In addition, the protein expressions of ATF3, Nrf2 and HO-1 in the IR group were increased than those in sham group. Compared with the IR group, ATF3 expressions in the IR+Fer-1 or IR+ATF3KD groups were decreased, and the protein contents of Nrf2 and HO-1 were further increased. Moreover, there were higher levels of M2 markers (Arg1, TGF-β and IL-10 mRNA) in the IR group than those in the sham group, and lower levels in the IR+Fer-1 group or in the IR+ATF3KD group compared with the IR group. The results of in vitro experiment are consistent with those of in vivo experiment. Mechanistically, the release of exosomes carrying miR-1306-5p by the HR group promoted more M2 macrophage.ConclusionATF3 might accelerate the ferroptosis by inhibiting Nrf2/ARE pathway, and exosomes from ferroptotic cells reduced the M1/M2 macrophage ratio, promoting fibrosis. |
| format | Article |
| id | doaj-art-4151512a915f469a8ee03e10d5a8fbac |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-4151512a915f469a8ee03e10d5a8fbac2025-02-05T07:32:08ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-02-011610.3389/fimmu.2025.15105001510500Exosomes secreted by ATF3/Nrf2-mediated ferroptotic renal tubular epithelial cells promote M1/M2 ratio imbalance inducing renal interstitial fibrosis following ischemia and reperfusion injuryQiao Tang0Jiatao Xie1Yifei Wang2Chong Dong3Chong Dong4Qian Sun5Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, ChinaThe First Clinical College of Wuhan University, Wuhan, ChinaDepartment of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, ChinaOrgan Transplantation Center, Tianjin First Central Hospital, Tianjin, ChinaTianjin Key Laboratory for Organ Transplantation, Tianjin, ChinaDepartment of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, ChinaBackgroundSevere renal ischemia and reperfusion injury (IRI) progresses to renal interstitial fibrosis (RIF) with limited therapeutic strategies. Although ferrptosis and macrophage polarization both play important roles in this model, their specific pathogenesis and interactions have not been elucidated. Therefore, we aimed to explore the mechanisms by which ferrotosis occurs in renal tubular epithelial cells (RTECs) and ferroptotic cell-derived exosomes induce macrophage polarization in IRI-related RIF model.MethodsIn vivo, C57BL/6J mice were randomly divided into four groups: sham group, ischemia and reperfusion (IR) group, IR + Ferrostatin-1 (Fer-1) group, and IR +ATF3 knockdown (ATFKD) group. In vitro, RTECs were divided into control (CON) group, hypoxia/reoxygenation (HR) group, HR +Fer-1 group, HR + siRNA-ATF3 (siATF3) group.ResultCompared with the sham group, the IR group showed more severe kidney injury in HE staining, more collagen fibers in Masson staining, and higher α-SMA expression levels in immunohistochemistry. Total iron and MDA content increased while GSH content decreased. The IR group had more significant mitochondrial damage and higher PTGS2 and TFRC mRNA levels than those in the sham group. Compared with the IR group, the above indexes were all alleviated in the IR+Fer-1 or IR+ATF3KD groups. In addition, the protein expressions of ATF3, Nrf2 and HO-1 in the IR group were increased than those in sham group. Compared with the IR group, ATF3 expressions in the IR+Fer-1 or IR+ATF3KD groups were decreased, and the protein contents of Nrf2 and HO-1 were further increased. Moreover, there were higher levels of M2 markers (Arg1, TGF-β and IL-10 mRNA) in the IR group than those in the sham group, and lower levels in the IR+Fer-1 group or in the IR+ATF3KD group compared with the IR group. The results of in vitro experiment are consistent with those of in vivo experiment. Mechanistically, the release of exosomes carrying miR-1306-5p by the HR group promoted more M2 macrophage.ConclusionATF3 might accelerate the ferroptosis by inhibiting Nrf2/ARE pathway, and exosomes from ferroptotic cells reduced the M1/M2 macrophage ratio, promoting fibrosis.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1510500/fullischemia and reperfusionrenal interstitial fibrosisferroptosisactivation transcription factor 3exosomemacrophages |
| spellingShingle | Qiao Tang Jiatao Xie Yifei Wang Chong Dong Chong Dong Qian Sun Exosomes secreted by ATF3/Nrf2-mediated ferroptotic renal tubular epithelial cells promote M1/M2 ratio imbalance inducing renal interstitial fibrosis following ischemia and reperfusion injury Frontiers in Immunology ischemia and reperfusion renal interstitial fibrosis ferroptosis activation transcription factor 3 exosome macrophages |
| title | Exosomes secreted by ATF3/Nrf2-mediated ferroptotic renal tubular epithelial cells promote M1/M2 ratio imbalance inducing renal interstitial fibrosis following ischemia and reperfusion injury |
| title_full | Exosomes secreted by ATF3/Nrf2-mediated ferroptotic renal tubular epithelial cells promote M1/M2 ratio imbalance inducing renal interstitial fibrosis following ischemia and reperfusion injury |
| title_fullStr | Exosomes secreted by ATF3/Nrf2-mediated ferroptotic renal tubular epithelial cells promote M1/M2 ratio imbalance inducing renal interstitial fibrosis following ischemia and reperfusion injury |
| title_full_unstemmed | Exosomes secreted by ATF3/Nrf2-mediated ferroptotic renal tubular epithelial cells promote M1/M2 ratio imbalance inducing renal interstitial fibrosis following ischemia and reperfusion injury |
| title_short | Exosomes secreted by ATF3/Nrf2-mediated ferroptotic renal tubular epithelial cells promote M1/M2 ratio imbalance inducing renal interstitial fibrosis following ischemia and reperfusion injury |
| title_sort | exosomes secreted by atf3 nrf2 mediated ferroptotic renal tubular epithelial cells promote m1 m2 ratio imbalance inducing renal interstitial fibrosis following ischemia and reperfusion injury |
| topic | ischemia and reperfusion renal interstitial fibrosis ferroptosis activation transcription factor 3 exosome macrophages |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1510500/full |
| work_keys_str_mv | AT qiaotang exosomessecretedbyatf3nrf2mediatedferroptoticrenaltubularepithelialcellspromotem1m2ratioimbalanceinducingrenalinterstitialfibrosisfollowingischemiaandreperfusioninjury AT jiataoxie exosomessecretedbyatf3nrf2mediatedferroptoticrenaltubularepithelialcellspromotem1m2ratioimbalanceinducingrenalinterstitialfibrosisfollowingischemiaandreperfusioninjury AT yifeiwang exosomessecretedbyatf3nrf2mediatedferroptoticrenaltubularepithelialcellspromotem1m2ratioimbalanceinducingrenalinterstitialfibrosisfollowingischemiaandreperfusioninjury AT chongdong exosomessecretedbyatf3nrf2mediatedferroptoticrenaltubularepithelialcellspromotem1m2ratioimbalanceinducingrenalinterstitialfibrosisfollowingischemiaandreperfusioninjury AT chongdong exosomessecretedbyatf3nrf2mediatedferroptoticrenaltubularepithelialcellspromotem1m2ratioimbalanceinducingrenalinterstitialfibrosisfollowingischemiaandreperfusioninjury AT qiansun exosomessecretedbyatf3nrf2mediatedferroptoticrenaltubularepithelialcellspromotem1m2ratioimbalanceinducingrenalinterstitialfibrosisfollowingischemiaandreperfusioninjury |