title: Transient receptor potential vanilloid type 4 channels mediate Na-K-Cl-co-transporter-induced brain edema after traumatic brain injury.
abstract: Na+-K+-2Cl-co-transporter (NKCC1) plays an important role in traumatic brain injury (TBI)-induced brain edema via the MAPK cascade. The transient receptor potential vanilloid type 4 (TRPV4) channel participates in neurogenic inflammation, pain transmission, and edema. In this study, we investigated the relationship between NKCC1 and TRPV4 and the related signaling pathways in TBI-induced brain edema and neuronal damage. TBI was induced by the calibrated weight-drop device. Adult male Wistar rats were randomly assigned into sham and experimental groups for time-course studies of TRPV4 expression after TBI. Hippocampal TRPV4, NKCC1, MAPK, and PI-3K cascades were analyzed by western blot, and brain edema was also evaluated among the different groups. Expression of hippocampal TRPV4 peaked at 8 h after TBI, and phosphorylation of the MAPK cascade and Akt was significantly elevated. Administration of either the TRPV4 antagonist, RN1734, or NKCC1 antagonist, bumetanide, significantly attenuated TBI-induced brain edema through decreasing the phosphorylation of MEK, ERK, and Akt proteins. Bumetanide injection inhibited TRPV4 expression, which suggests NKCC1 activation is critical to TRPV4 activation. Our results showed that hippocampal NKCC1 activation increased TRPV4 expression after TBI and then induced severe brain edema and neuronal damage through activation of the MAPK cascade and Akt-related signaling pathway.
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei, Taiwan.
authors.forename: Kwok-Tung
authors.initials: KT
authors.lastname: Lu
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei, Taiwan.
authors.forename: Tai-Chun
authors.initials: TC
authors.lastname: Huang
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei, Taiwan.
authors.forename: Ya-Hsin
authors.initials: YH
authors.lastname: Tsai
authors.affiliation: Institute of Biochemical Science and Technology, National Chia-Yi University, Chia-Yi, Taiwan.
authors.forename: Yi-Ling
authors.initials: YL
authors.lastname: Yang
mesh_terms: D000818:Animals; D001834:Body Water / Q000378:metabolism; D001921:Brain / Q000473:pathology; D001929:Brain Edema / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism*; D000070642:Brain Injuries, Traumatic / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism*; D002034:Bumetanide / Q000008:administration & dosage / Q000627:therapeutic use; D006624:Hippocampus / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051058:Oncogene Protein v-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D064506:Solute Carrier Family 12, Member 2 / Q000378:metabolism*; D013449:Sulfonamides / Q000008:administration & dosage / Q000627:therapeutic use; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C544743:RN 1734; C578879:Slc12a2 protein, rat; D064506:Solute Carrier Family 12, Member 2; D013449:Sulfonamides; D050916:TRPV Cation Channels; C486577:Trpv4 protein, rat; D002034:Bumetanide; D051058:Oncogene Protein v-akt
keywords: NKCC1; TRPV4; brain edema; mitogen-activated protein kinases cascade; traumatic brain injury