title: Foxo3a transcriptionally upregulates AQP4 and induces cerebral edema following traumatic brain injury.
abstract: Increased cranial pressure due to development of edema contributes significantly to the pathology of traumatic brain injury (TBI). Induction of an astrocytic water channel protein, Aquaporin 4 (AQP4), is known to predominantly contribute to cytotoxic edema following TBI. However, the mechanism for the increase in AQP4 following 24 h of TBI is poorly understood. Here we show that transcriptional activation of a ubiquitously expressed mammalian forkhead transcription factor, Foxo3a, induces cerebral edema by increasing the AQP4 level in the controlled cortical impact model of TBI in mice. TBI stimulates nuclear translocation of Foxo3a in astrocytes and subsequently augments its binding to AQP4 promoter in pericontusional cortex. Nuclear accumulation of Foxo3a is augmented by a decrease in phosphorylation at its Ser256 residue due to inactivation of Akt after TBI. Depletion of Foxo3a in mice rescues cytotoxic edema by preventing induction of AQP4 as well as attenuates memory impairment after TBI in mice.
authors.affiliation: Institute of Molecular Medicine and Genetics and Department of Neurology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912.
authors.forename: Suraj
authors.initials: S
authors.lastname: Kapoor
authors.forename: Seon-Myung
authors.initials: SM
authors.lastname: Kim
authors.forename: Justin M
authors.initials: JM
authors.lastname: Farook
authors.forename: Sajad
authors.initials: S
authors.lastname: Mir
authors.forename: Rahul
authors.initials: R
authors.lastname: Saha
authors.forename: Nilkantha
authors.initials: N
authors.lastname: Sen
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics; D000818:Animals; D051401:Aquaporin 4 / Q000096:biosynthesis* / Q000235:genetics; D001483:Base Sequence; D001929:Brain Edema / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D001930:Brain Injuries / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010766:Phosphorylation / Q000235:genetics; D014158:Transcription, Genetic; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology*
chemical_list: C496031:Aqp4 protein, mouse; D051401:Aquaporin 4; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse