Targeting Mechanosensitive Piezo1 Alleviated Renal Fibrosis Through p38MAPK-YAP Pathway
Renal fibrosis is the most common pathological manifestation of a wide variety of chronic kidney disease. Increased extracellular matrix (ECM) secretion and enhanced microenvironment stiffening aggravate the progression of renal fibrosis. However, the related mechanisms remain unclear. Here, we eval...
Guardado en:
| Autores principales: | , , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Frontiers Media S.A.
2021
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/db3a283c7c494c4f814e77464921bdf5 |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:db3a283c7c494c4f814e77464921bdf5 |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:db3a283c7c494c4f814e77464921bdf52021-11-05T08:05:52ZTargeting Mechanosensitive Piezo1 Alleviated Renal Fibrosis Through p38MAPK-YAP Pathway2296-634X10.3389/fcell.2021.741060https://doaj.org/article/db3a283c7c494c4f814e77464921bdf52021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fcell.2021.741060/fullhttps://doaj.org/toc/2296-634XRenal fibrosis is the most common pathological manifestation of a wide variety of chronic kidney disease. Increased extracellular matrix (ECM) secretion and enhanced microenvironment stiffening aggravate the progression of renal fibrosis. However, the related mechanisms remain unclear. Here, we evaluated the mechanism by which ECM stiffness aggravates renal fibrosis. In the present study, renal mesangial cells (MCs) were cultured on polyacrylamide hydrogels with different stiffness accurately detected by atomic force microscope (AFM), simulating the in vivo growth microenvironment of MCs in normal kidney and renal fibrosis. A series of in vitro knockdown and activation experiments were performed to establish the signaling pathway responsible for mechanics-induced MCs activation. In addition, an animal model of renal fibrosis was established in mice induced by unilateral ureteral obstruction (UUO). Lentiviral particles containing short hairpin RNA (sh RNA) targeting Piezo1 were used to explore the effect of Piezo1 knockdown on matrix stiffness-induced MCs activation and UUO-induced renal fibrosis. An in vitro experiment demonstrated that elevated ECM stiffness triggered the activation of Piezo1, which increased YAP nuclear translocation through the p38MAPK, and consequently led to increased ECM secretion. Furthermore, these consequences have been verified in the animal model of renal fibrosis induced by UUO and Piezo1 knockdown could alleviate UUO-induced fibrosis and improve renal function in vivo. Collectively, our results for the first time demonstrate enhanced matrix stiffness aggravates the progression of renal fibrosis through the Piezo1-p38MAPK-YAP pathway. Targeting mechanosensitive Piezo1 might be a potential therapeutic strategy for delaying the progression of renal fibrosis.Yuanyuan FuPengzhi WanJie ZhangXue LiJia XingYu ZouKaiyue WangHui PengHui PengQizhuo ZhuLiu CaoXiaoyue ZhaiXiaoyue ZhaiFrontiers Media S.A.articlerenal fibrosismatrix stiffnessextracellular matrix secreationPiezo1YAPBiology (General)QH301-705.5ENFrontiers in Cell and Developmental Biology, Vol 9 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
renal fibrosis matrix stiffness extracellular matrix secreation Piezo1 YAP Biology (General) QH301-705.5 |
| spellingShingle |
renal fibrosis matrix stiffness extracellular matrix secreation Piezo1 YAP Biology (General) QH301-705.5 Yuanyuan Fu Pengzhi Wan Jie Zhang Xue Li Jia Xing Yu Zou Kaiyue Wang Hui Peng Hui Peng Qizhuo Zhu Liu Cao Xiaoyue Zhai Xiaoyue Zhai Targeting Mechanosensitive Piezo1 Alleviated Renal Fibrosis Through p38MAPK-YAP Pathway |
| description |
Renal fibrosis is the most common pathological manifestation of a wide variety of chronic kidney disease. Increased extracellular matrix (ECM) secretion and enhanced microenvironment stiffening aggravate the progression of renal fibrosis. However, the related mechanisms remain unclear. Here, we evaluated the mechanism by which ECM stiffness aggravates renal fibrosis. In the present study, renal mesangial cells (MCs) were cultured on polyacrylamide hydrogels with different stiffness accurately detected by atomic force microscope (AFM), simulating the in vivo growth microenvironment of MCs in normal kidney and renal fibrosis. A series of in vitro knockdown and activation experiments were performed to establish the signaling pathway responsible for mechanics-induced MCs activation. In addition, an animal model of renal fibrosis was established in mice induced by unilateral ureteral obstruction (UUO). Lentiviral particles containing short hairpin RNA (sh RNA) targeting Piezo1 were used to explore the effect of Piezo1 knockdown on matrix stiffness-induced MCs activation and UUO-induced renal fibrosis. An in vitro experiment demonstrated that elevated ECM stiffness triggered the activation of Piezo1, which increased YAP nuclear translocation through the p38MAPK, and consequently led to increased ECM secretion. Furthermore, these consequences have been verified in the animal model of renal fibrosis induced by UUO and Piezo1 knockdown could alleviate UUO-induced fibrosis and improve renal function in vivo. Collectively, our results for the first time demonstrate enhanced matrix stiffness aggravates the progression of renal fibrosis through the Piezo1-p38MAPK-YAP pathway. Targeting mechanosensitive Piezo1 might be a potential therapeutic strategy for delaying the progression of renal fibrosis. |
| format |
article |
| author |
Yuanyuan Fu Pengzhi Wan Jie Zhang Xue Li Jia Xing Yu Zou Kaiyue Wang Hui Peng Hui Peng Qizhuo Zhu Liu Cao Xiaoyue Zhai Xiaoyue Zhai |
| author_facet |
Yuanyuan Fu Pengzhi Wan Jie Zhang Xue Li Jia Xing Yu Zou Kaiyue Wang Hui Peng Hui Peng Qizhuo Zhu Liu Cao Xiaoyue Zhai Xiaoyue Zhai |
| author_sort |
Yuanyuan Fu |
| title |
Targeting Mechanosensitive Piezo1 Alleviated Renal Fibrosis Through p38MAPK-YAP Pathway |
| title_short |
Targeting Mechanosensitive Piezo1 Alleviated Renal Fibrosis Through p38MAPK-YAP Pathway |
| title_full |
Targeting Mechanosensitive Piezo1 Alleviated Renal Fibrosis Through p38MAPK-YAP Pathway |
| title_fullStr |
Targeting Mechanosensitive Piezo1 Alleviated Renal Fibrosis Through p38MAPK-YAP Pathway |
| title_full_unstemmed |
Targeting Mechanosensitive Piezo1 Alleviated Renal Fibrosis Through p38MAPK-YAP Pathway |
| title_sort |
targeting mechanosensitive piezo1 alleviated renal fibrosis through p38mapk-yap pathway |
| publisher |
Frontiers Media S.A. |
| publishDate |
2021 |
| url |
https://doaj.org/article/db3a283c7c494c4f814e77464921bdf5 |
| work_keys_str_mv |
AT yuanyuanfu targetingmechanosensitivepiezo1alleviatedrenalfibrosisthroughp38mapkyappathway AT pengzhiwan targetingmechanosensitivepiezo1alleviatedrenalfibrosisthroughp38mapkyappathway AT jiezhang targetingmechanosensitivepiezo1alleviatedrenalfibrosisthroughp38mapkyappathway AT xueli targetingmechanosensitivepiezo1alleviatedrenalfibrosisthroughp38mapkyappathway AT jiaxing targetingmechanosensitivepiezo1alleviatedrenalfibrosisthroughp38mapkyappathway AT yuzou targetingmechanosensitivepiezo1alleviatedrenalfibrosisthroughp38mapkyappathway AT kaiyuewang targetingmechanosensitivepiezo1alleviatedrenalfibrosisthroughp38mapkyappathway AT huipeng targetingmechanosensitivepiezo1alleviatedrenalfibrosisthroughp38mapkyappathway AT huipeng targetingmechanosensitivepiezo1alleviatedrenalfibrosisthroughp38mapkyappathway AT qizhuozhu targetingmechanosensitivepiezo1alleviatedrenalfibrosisthroughp38mapkyappathway AT liucao targetingmechanosensitivepiezo1alleviatedrenalfibrosisthroughp38mapkyappathway AT xiaoyuezhai targetingmechanosensitivepiezo1alleviatedrenalfibrosisthroughp38mapkyappathway AT xiaoyuezhai targetingmechanosensitivepiezo1alleviatedrenalfibrosisthroughp38mapkyappathway |
| _version_ |
1718444501230419968 |