Yifan Ren, Qing Cui, Wuming Liu, Hangcheng Liu, Tao Wang, Hongwei Lu, Yi Lv, Rongqian Wu
{"title":"阻断TRPM4可通过NMDA受体依赖途径减轻急性胰腺炎中胰腺腺泡细胞的损伤。","authors":"Yifan Ren, Qing Cui, Wuming Liu, Hangcheng Liu, Tao Wang, Hongwei Lu, Yi Lv, Rongqian Wu","doi":"10.7150/thno.116520","DOIUrl":null,"url":null,"abstract":"<p><p><b>Background:</b> Mitochondrial dysfunction caused by Ca<sup>2+</sup> overload in pancreatic acinar cells is an important mechanism in the pathogenesis of acute pancreatitis (AP). Transient receptor potential cation channel melastatin 4 (TRPM4), a non-selective cation channel, can be activated by intracellular Ca<sup>2+</sup>, and is involved in mediating damage to neuronal mitochondrial function. However, the role of TRPM4 activation in mitochondrial dysfunction during AP remains unknown. <b>Methods:</b> We employed three mouse models of AP (intraperitoneal administration of L-arginine, cerulein plus lipopolysaccharides (LPS), or cerulein alone) for <i>in vivo</i> studies. For <i>in vitro</i> studies, cerulein+ LPS was used to induce mitochondrial dysfunction and cell death in AR42J cell. <i>Trpm4</i> gene-defective mice and plasmids were utilized to downregulate the expression of TRPM4 in mice or overexpress TRPM4 in AR42J. 9-Phenanthrol, a specific inhibitor of TRPM4, was used to antagonize TRPM4 activity both <i>in vitro</i> and <i>in vivo</i>. <b>Results:</b> Pancreatic TRPM4 levels were increased in all three AP models. Blocking TRPM4 activity with 9-phenanthrol or knocking down TRPM4 expression alleviated pancreatic damage and reduced mortality in AP mice. The protective effect of TRPM4 defects on AP was associated with improved mitochondrial function in pancreatic acinar cells. Mechanistically, TRPM4 activation induced mitochondrial dysfunction and cell death in AP were dependent on the presence of N-methyl-D-aspartate receptors (NMDARs). Blocking NMDARs mitigates the aggravated mitochondrial damage, ER stress and cell death caused by TRPM4 activation in AP. <b>Conclusions:</b> TRPM4 activation contributes to pancreatic acinar cells damage via an NMDAs-dependent pathway in AP. The TRPM4/NMDARs complex provides a new target for the future treatment of AP.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 14","pages":"6901-6918"},"PeriodicalIF":12.4000,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12203808/pdf/","citationCount":"0","resultStr":"{\"title\":\"Blocking TRPM4 alleviates pancreatic acinar cell damage via an NMDA receptor-dependent pathway in acute pancreatitis.\",\"authors\":\"Yifan Ren, Qing Cui, Wuming Liu, Hangcheng Liu, Tao Wang, Hongwei Lu, Yi Lv, Rongqian Wu\",\"doi\":\"10.7150/thno.116520\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p><b>Background:</b> Mitochondrial dysfunction caused by Ca<sup>2+</sup> overload in pancreatic acinar cells is an important mechanism in the pathogenesis of acute pancreatitis (AP). Transient receptor potential cation channel melastatin 4 (TRPM4), a non-selective cation channel, can be activated by intracellular Ca<sup>2+</sup>, and is involved in mediating damage to neuronal mitochondrial function. However, the role of TRPM4 activation in mitochondrial dysfunction during AP remains unknown. <b>Methods:</b> We employed three mouse models of AP (intraperitoneal administration of L-arginine, cerulein plus lipopolysaccharides (LPS), or cerulein alone) for <i>in vivo</i> studies. For <i>in vitro</i> studies, cerulein+ LPS was used to induce mitochondrial dysfunction and cell death in AR42J cell. <i>Trpm4</i> gene-defective mice and plasmids were utilized to downregulate the expression of TRPM4 in mice or overexpress TRPM4 in AR42J. 9-Phenanthrol, a specific inhibitor of TRPM4, was used to antagonize TRPM4 activity both <i>in vitro</i> and <i>in vivo</i>. <b>Results:</b> Pancreatic TRPM4 levels were increased in all three AP models. Blocking TRPM4 activity with 9-phenanthrol or knocking down TRPM4 expression alleviated pancreatic damage and reduced mortality in AP mice. The protective effect of TRPM4 defects on AP was associated with improved mitochondrial function in pancreatic acinar cells. Mechanistically, TRPM4 activation induced mitochondrial dysfunction and cell death in AP were dependent on the presence of N-methyl-D-aspartate receptors (NMDARs). Blocking NMDARs mitigates the aggravated mitochondrial damage, ER stress and cell death caused by TRPM4 activation in AP. <b>Conclusions:</b> TRPM4 activation contributes to pancreatic acinar cells damage via an NMDAs-dependent pathway in AP. The TRPM4/NMDARs complex provides a new target for the future treatment of AP.</p>\",\"PeriodicalId\":22932,\"journal\":{\"name\":\"Theranostics\",\"volume\":\"15 14\",\"pages\":\"6901-6918\"},\"PeriodicalIF\":12.4000,\"publicationDate\":\"2025-06-09\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12203808/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Theranostics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.7150/thno.116520\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q1\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Theranostics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.7150/thno.116520","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0
摘要
背景:胰腺腺泡细胞Ca2+超载引起的线粒体功能障碍是急性胰腺炎(AP)发病的重要机制。瞬时受体电位阳离子通道美拉他汀4 (TRPM4)是一种非选择性阳离子通道,可被细胞内Ca2+激活,并参与介导神经元线粒体功能的损伤。然而,TRPM4激活在AP期间线粒体功能障碍中的作用尚不清楚。方法:采用三种AP小鼠模型(腹腔注射l -精氨酸、蓝蛋白加脂多糖(LPS)或单独注射蓝蛋白)进行体内研究。在体外研究中,我们使用cerulein+ LPS诱导AR42J细胞线粒体功能障碍和细胞死亡。利用Trpm4基因缺陷小鼠和质粒下调小鼠中Trpm4的表达或过表达AR42J中的Trpm4。9-Phenanthrol是TRPM4的特异性抑制剂,在体外和体内均可拮抗TRPM4活性。结果:三种AP模型胰腺TRPM4水平均升高。用9-菲罗酚阻断TRPM4活性或抑制TRPM4表达可减轻AP小鼠的胰腺损伤并降低死亡率。TRPM4缺陷对AP的保护作用与胰腺腺泡细胞线粒体功能的改善有关。在机制上,TRPM4激活诱导AP线粒体功能障碍和细胞死亡依赖于n -甲基- d -天冬氨酸受体(NMDARs)的存在。阻断NMDARs可减轻由TRPM4激活引起的AP中线粒体损伤、内质网应激和细胞死亡的加重。结论:TRPM4激活在AP中通过nmdas依赖途径参与胰腺腺泡细胞损伤,TRPM4/NMDARs复合物为AP的未来治疗提供了新的靶点。
Blocking TRPM4 alleviates pancreatic acinar cell damage via an NMDA receptor-dependent pathway in acute pancreatitis.
Background: Mitochondrial dysfunction caused by Ca2+ overload in pancreatic acinar cells is an important mechanism in the pathogenesis of acute pancreatitis (AP). Transient receptor potential cation channel melastatin 4 (TRPM4), a non-selective cation channel, can be activated by intracellular Ca2+, and is involved in mediating damage to neuronal mitochondrial function. However, the role of TRPM4 activation in mitochondrial dysfunction during AP remains unknown. Methods: We employed three mouse models of AP (intraperitoneal administration of L-arginine, cerulein plus lipopolysaccharides (LPS), or cerulein alone) for in vivo studies. For in vitro studies, cerulein+ LPS was used to induce mitochondrial dysfunction and cell death in AR42J cell. Trpm4 gene-defective mice and plasmids were utilized to downregulate the expression of TRPM4 in mice or overexpress TRPM4 in AR42J. 9-Phenanthrol, a specific inhibitor of TRPM4, was used to antagonize TRPM4 activity both in vitro and in vivo. Results: Pancreatic TRPM4 levels were increased in all three AP models. Blocking TRPM4 activity with 9-phenanthrol or knocking down TRPM4 expression alleviated pancreatic damage and reduced mortality in AP mice. The protective effect of TRPM4 defects on AP was associated with improved mitochondrial function in pancreatic acinar cells. Mechanistically, TRPM4 activation induced mitochondrial dysfunction and cell death in AP were dependent on the presence of N-methyl-D-aspartate receptors (NMDARs). Blocking NMDARs mitigates the aggravated mitochondrial damage, ER stress and cell death caused by TRPM4 activation in AP. Conclusions: TRPM4 activation contributes to pancreatic acinar cells damage via an NMDAs-dependent pathway in AP. The TRPM4/NMDARs complex provides a new target for the future treatment of AP.
期刊介绍:
Theranostics serves as a pivotal platform for the exchange of clinical and scientific insights within the diagnostic and therapeutic molecular and nanomedicine community, along with allied professions engaged in integrating molecular imaging and therapy. As a multidisciplinary journal, Theranostics showcases innovative research articles spanning fields such as in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor technology, nanobiosensors, bioelectronics, system biology, translational medicine, point-of-care applications, and personalized medicine. Encouraging a broad spectrum of biomedical research with potential theranostic applications, the journal rigorously peer-reviews primary research, alongside publishing reviews, news, and commentary that aim to bridge the gap between the laboratory, clinic, and biotechnology industries.