Ma Qingjie, Wu Jilin, Li Huixian, Yin Renwan, Yang Wenjing, Luo Jia, Bai Yuncheng, Liu Na
Department of Anesthesiology, The First People's Hospital of Yunnan Province. The Affiliated Hospital of Kunming University of Science and Technology, Kunming, China.
Department of Anesthesiology, Kunming Children's Hospital, Kunming, China.
Tissue Cell. 2025 Oct;96:103019. doi: 10.1016/j.tice.2025.103019. Epub 2025 Jun 16.
Transient receptor potential vanilloid 4 (TRPV4) is a nonselective calcium-permeable cation channel. Our previous study revealed that TRPV4 mediates endoplasmic reticulum (ER) stress and inflammation, leading to the loss of dopamine neurons in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD) model mice.
The aim of the present study was to investigate the molecular role of TRPV4 in ferroptosis in PD models.
We used GSK2193874 (an inhibitor of TRPV4) and siRNA targeting TRPV4 to explore the role of TRPV4 in iron transportation, the production of reactive oxygen species (ROS) and oxidative stress in 1-methyl-4-phenylpyridinium ion (MPP)-treated PC12 cells by H2DCFDA, CCK-8, ELISA and western blot. In a PD mouse model, the intracerebral injection of adeno-associated virus (AAV) was used to knockdown or upregulate TRPV4 expression following the intraperitoneal injection of MPTP and GSK2193874. We used Perl's iron staining and western blot to detect alterations in iron-positive cells and ferroptosis-associated molecules in the substantia nigra (SN).
We found that silencing TRPV4 increased the expression of glutathione peroxidase 4 (GPX4) and ferritin heavy chain (FTH1), decreased divalent metal transporter 1 (DMT1), and alleviated the excessive ROS and oxidative stress in MPP-induced PC12 cells. Moreover, TRPV4 regulated the accumulation of iron in the SN and ferroptosis-associated signalling pathways in PD mice.
TRPV4 plays a key role in MPP/MPTP-induced ferroptosis. Our results indicate that the downregulation of TRPV4 may a represent promising treatment for PD through the inhibition of ferroptosis.
瞬时受体电位香草酸受体4（TRPV4）是一种非选择性的钙通透性阳离子通道。我们之前的研究表明，TRPV4介导内质网（ER）应激和炎症，导致1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的帕金森病（PD）模型小鼠中多巴胺神经元的丢失。
本研究旨在探讨TRPV4在PD模型铁死亡中的分子作用。
我们使用GSK2193874（TRPV4抑制剂）和靶向TRPV4的小干扰RNA（siRNA），通过H2DCFDA、CCK-8、酶联免疫吸附测定（ELISA）和蛋白质免疫印迹法，探讨TRPV4在1-甲基-4-苯基吡啶离子（MPP）处理的PC12细胞中铁转运、活性氧（ROS）产生和氧化应激中的作用。在PD小鼠模型中，腹腔注射MPTP和GSK2193874后，通过脑内注射腺相关病毒（AAV）来敲低或上调TRPV4表达。我们使用Perl铁染色和蛋白质免疫印迹法检测黑质（SN）中铁阳性细胞和铁死亡相关分子的变化。
我们发现，沉默TRPV4可增加谷胱甘肽过氧化物酶4（GPX4）和铁蛋白重链（FTH1）的表达，降低二价金属转运体1（DMT1），并减轻MPP诱导的PC12细胞中过量的ROS和氧化应激。此外，TRPV4调节PD小鼠SN中铁的积累和铁死亡相关信号通路。
TRPV4在MPP/MPTP诱导的铁死亡中起关键作用。我们的结果表明，下调TRPV4可能是一种通过抑制铁死亡治疗PD的有前景的方法。
