Piezo1 disrupts blood–brain barrier via CaMKII/Nrf2 in ischemic stroke
Abstract Ischemic stroke (IS) leads to the disruption of blood–brain barrier (BBB) integrity, resulting in brain edema. In this process, endothelial cells, as a crucial component of the BBB, are subjected to external pressure and tensile stress. Piezo1, a mechanically-sensitive ion channel, may be a...
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2025-06-01
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| Series: | Cellular and Molecular Life Sciences |
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| Online Access: | https://doi.org/10.1007/s00018-025-05804-8 |
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| author | Huimin Fu Yang Yu Shangyuan Wang Peixian Xu Yuting Sun Jiaqi Li Xiaoli Ge Shuming Pan |
| author_facet | Huimin Fu Yang Yu Shangyuan Wang Peixian Xu Yuting Sun Jiaqi Li Xiaoli Ge Shuming Pan |
| author_sort | Huimin Fu |
| collection | DOAJ |
| description | Abstract Ischemic stroke (IS) leads to the disruption of blood–brain barrier (BBB) integrity, resulting in brain edema. In this process, endothelial cells, as a crucial component of the BBB, are subjected to external pressure and tensile stress. Piezo1, a mechanically-sensitive ion channel, may be activated by sensing these stresses, further exacerbating the destruction of the BBB. Our findings indicated that after cerebral ischemia/reperfusion (I/R) injury, the expression of Piezo1 in endothelial cells increased. In endothelial-specific Piezo1 knockout (Piezo1 ECKO) mice, brain damage, neurological deficits, and BBB disruption caused by I/R injury were significantly alleviated. Moreover, oxidative stress and the inflammatory response in the cerebral cortex induced by I/R were also reduced. In vitro, by activating or knocking out Piezo1 in bEnd.3 cells under oxygen–glucose deprivation/reperfusion (OGD/R), we observed similar effects, further corroborating the in vivo findings. To elucidate the molecular mechanism, we found that the protective effect of Piezo1 deficiency on BBB integrity is mediated by the alleviation of p-CaMKII and the enhancement of Nrf2 nuclear translocation. This, in turn, leads to the upregulation of NQO-1 and HO-1 expression. In summary, our research indicates that Piezo1 exacerbates BBB disruption after cerebral I/R injury by promoting oxidative stress, inflammation, and mitochondrial dysfunction. This process is closely linked to the activation of the Ca2+/CaMKII and Nrf2 pathways, suggesting that Piezo1 may be a potential therapeutic target for IS. |
| format | Article |
| id | doaj-art-fb852be12ac840a2a2084d5d52a15705 |
| institution | Kabale University |
| issn | 1420-9071 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Springer |
| record_format | Article |
| series | Cellular and Molecular Life Sciences |
| spelling | doaj-art-fb852be12ac840a2a2084d5d52a157052025-08-20T03:31:44ZengSpringerCellular and Molecular Life Sciences1420-90712025-06-0182111910.1007/s00018-025-05804-8Piezo1 disrupts blood–brain barrier via CaMKII/Nrf2 in ischemic strokeHuimin Fu0Yang Yu1Shangyuan Wang2Peixian Xu3Yuting Sun4Jiaqi Li5Xiaoli Ge6Shuming Pan7Department of Emergency, Xinhua Hospital Affiliated to Shanghai Jiao Tong University, School of MedicineDepartment of Emergency, Xinhua Hospital Affiliated to Shanghai Jiao Tong University, School of MedicineDepartment of Emergency, Xinhua Hospital Affiliated to Shanghai Jiao Tong University, School of MedicineDepartment of Emergency, Xinhua Hospital Affiliated to Shanghai Jiao Tong University, School of MedicineDepartment of Emergency, Putuo, Hospital Shanghai University of Traditional Chinese MedicineDepartment of Emergency, Putuo, Hospital Shanghai University of Traditional Chinese MedicineDepartment of Emergency, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University, School of MedicineDepartment of Emergency, Xinhua Hospital Affiliated to Shanghai Jiao Tong University, School of MedicineAbstract Ischemic stroke (IS) leads to the disruption of blood–brain barrier (BBB) integrity, resulting in brain edema. In this process, endothelial cells, as a crucial component of the BBB, are subjected to external pressure and tensile stress. Piezo1, a mechanically-sensitive ion channel, may be activated by sensing these stresses, further exacerbating the destruction of the BBB. Our findings indicated that after cerebral ischemia/reperfusion (I/R) injury, the expression of Piezo1 in endothelial cells increased. In endothelial-specific Piezo1 knockout (Piezo1 ECKO) mice, brain damage, neurological deficits, and BBB disruption caused by I/R injury were significantly alleviated. Moreover, oxidative stress and the inflammatory response in the cerebral cortex induced by I/R were also reduced. In vitro, by activating or knocking out Piezo1 in bEnd.3 cells under oxygen–glucose deprivation/reperfusion (OGD/R), we observed similar effects, further corroborating the in vivo findings. To elucidate the molecular mechanism, we found that the protective effect of Piezo1 deficiency on BBB integrity is mediated by the alleviation of p-CaMKII and the enhancement of Nrf2 nuclear translocation. This, in turn, leads to the upregulation of NQO-1 and HO-1 expression. In summary, our research indicates that Piezo1 exacerbates BBB disruption after cerebral I/R injury by promoting oxidative stress, inflammation, and mitochondrial dysfunction. This process is closely linked to the activation of the Ca2+/CaMKII and Nrf2 pathways, suggesting that Piezo1 may be a potential therapeutic target for IS.https://doi.org/10.1007/s00018-025-05804-8Endothelial dysfunctionOxidative stressNeuroinflammationMitochondrial dysfunction |
| spellingShingle | Huimin Fu Yang Yu Shangyuan Wang Peixian Xu Yuting Sun Jiaqi Li Xiaoli Ge Shuming Pan Piezo1 disrupts blood–brain barrier via CaMKII/Nrf2 in ischemic stroke Cellular and Molecular Life Sciences Endothelial dysfunction Oxidative stress Neuroinflammation Mitochondrial dysfunction |
| title | Piezo1 disrupts blood–brain barrier via CaMKII/Nrf2 in ischemic stroke |
| title_full | Piezo1 disrupts blood–brain barrier via CaMKII/Nrf2 in ischemic stroke |
| title_fullStr | Piezo1 disrupts blood–brain barrier via CaMKII/Nrf2 in ischemic stroke |
| title_full_unstemmed | Piezo1 disrupts blood–brain barrier via CaMKII/Nrf2 in ischemic stroke |
| title_short | Piezo1 disrupts blood–brain barrier via CaMKII/Nrf2 in ischemic stroke |
| title_sort | piezo1 disrupts blood brain barrier via camkii nrf2 in ischemic stroke |
| topic | Endothelial dysfunction Oxidative stress Neuroinflammation Mitochondrial dysfunction |
| url | https://doi.org/10.1007/s00018-025-05804-8 |
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