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The transient receptor potential vanilloid type 4 (<jats:styled-content style=\"fixed-case\">TRPV<\/jats:styled-content>4) channel participates in neurogenic inflammation, pain transmission, and edema. In this study, we investigated the relationship between <jats:styled-content style=\"fixed-case\">NKCC<\/jats:styled-content>1 and <jats:styled-content style=\"fixed-case\">TRPV<\/jats:styled-content>4 and the related signaling pathways in <jats:styled-content style=\"fixed-case\">TBI<\/jats:styled-content>\u2010induced brain edema and neuronal damage. <jats:styled-content style=\"fixed-case\">TBI<\/jats:styled-content> was induced by the calibrated weight\u2010drop device. Adult male Wistar rats were randomly assigned into sham and experimental groups for time\u2010course studies of <jats:styled-content style=\"fixed-case\">TRPV<\/jats:styled-content>4 expression after <jats:styled-content style=\"fixed-case\">TBI<\/jats:styled-content>. Hippocampal <jats:styled-content style=\"fixed-case\">TRPV<\/jats:styled-content>4, <jats:styled-content style=\"fixed-case\">NKCC<\/jats:styled-content>1, <jats:styled-content style=\"fixed-case\">MAPK<\/jats:styled-content>, and <jats:styled-content style=\"fixed-case\">PI<\/jats:styled-content>\u20103K cascades were analyzed by western blot, and brain edema was also evaluated among the different groups. Expression of hippocampal <jats:styled-content style=\"fixed-case\">TRPV<\/jats:styled-content>4 peaked at 8\u00a0h after <jats:styled-content style=\"fixed-case\">TBI<\/jats:styled-content>, and phosphorylation of the <jats:styled-content style=\"fixed-case\">MAPK<\/jats:styled-content> cascade and Akt was significantly elevated. Administration of either the <jats:styled-content style=\"fixed-case\">TRPV<\/jats:styled-content>4 antagonist, <jats:styled-content style=\"fixed-case\">RN<\/jats:styled-content>1734, or <jats:styled-content style=\"fixed-case\">NKCC<\/jats:styled-content>1 antagonist, bumetanide, significantly attenuated <jats:styled-content style=\"fixed-case\">TBI<\/jats:styled-content>\u2010induced brain edema through decreasing the phosphorylation of <jats:styled-content style=\"fixed-case\">MEK<\/jats:styled-content>,<jats:styled-content style=\"fixed-case\"> ERK<\/jats:styled-content>, and Akt proteins. Bumetanide injection inhibited <jats:styled-content style=\"fixed-case\">TRPV<\/jats:styled-content>4 expression, which suggests <jats:styled-content style=\"fixed-case\">NKCC<\/jats:styled-content>1 activation is critical to <jats:styled-content style=\"fixed-case\">TRPV<\/jats:styled-content>4 activation. Our results showed that hippocampal <jats:styled-content style=\"fixed-case\">NKCC<\/jats:styled-content>1 activation increased <jats:styled-content style=\"fixed-case\">TRPV<\/jats:styled-content>4 expression after <jats:styled-content style=\"fixed-case\">TBI<\/jats:styled-content> and then induced severe brain edema and neuronal damage through activation of the <jats:styled-content style=\"fixed-case\">MAPK<\/jats:styled-content> cascade and Akt\u2010related signaling pathway.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc13920-fig-0009-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.13920","type":"journal-article","created":{"date-parts":[[2016,12,7]],"date-time":"2016-12-07T22:13:18Z","timestamp":1481148798000},"page":"718-727","source":"Crossref","is-referenced-by-count":55,"title":["Transient receptor potential vanilloid type 4 channels mediate Na\u2010K\u2010Cl\u2010co\u2010transporter\u2010induced brain edema after traumatic brain injury"],"prefix":"10.1111","volume":"140","author":[{"given":"Kwok\u2010Tung","family":"Lu","sequence":"first","affiliation":[{"name":"Department of Life Science National Taiwan Normal University Taipei Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tai\u2010Chun","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Life Science National Taiwan Normal University Taipei Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ya\u2010Hsin","family":"Tsai","sequence":"additional","affiliation":[{"name":"Department of Life Science National Taiwan Normal University Taipei Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi\u2010Ling","family":"Yang","sequence":"additional","affiliation":[{"name":"Institute of Biochemical Science and Technology National Chia\u2010Yi University Chia\u2010Yi Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2017,2,15]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(03)00462-8"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5385-05.2006"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2012.02186.x"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/0014-2999(90)90430-E"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/jcbfm.2010.168"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuro.2010.01.001"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1089\/neu.1997.14.839"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2007.06.039"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1012867108"},{"key":"e_1_2_8_11_1","first-page":"286","article-title":"The time course of vasogenic oedema after focal human head injury\u2013evidence from SPECT mapping of blood brain barrier defects","volume":"51","author":"Bullock R.","year":"1990","journal-title":"Acta Neurochir. 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