title: p53-induced uncoupling expression of aquaporin-4 and inwardly rectifying K+ 4.1 channels in cytotoxic edema after subarachnoid hemorrhage.
abstract: OBJECTIVE
  To investigate the mechanism behind cytotoxic edema formation following subarachnoid hemorrhage (SAH).
  
  
  METHODS
  We explored the role of aquaporin-4 (AQP4), inwardly rectifying K(+) 4.1 (Kir4.1) channels and their upstream orchestrators p53 and p38MAPK in this process. A p53 inhibitor, pifithrin-α (PFT-α) was administered intraperitoneally to rats undergoing SAH by endovascular perforation. Totally, 98 male SD rats were categorized into sham, SAH, SAH+ dimethyl sulfoxide (DMSO), SAH+ 0.2 or 2.0 mg/kg PFT-α groups. At 24 h after SAH, MRI (diffusion-weighted imaging [DWI]), immunohistochemistry, and Western blot were used.
  
  
  RESULTS
  MRI (DWI) showed a significant cytotoxic edema in the brain following SAH with PFT-α therapy reducing it. Immunohistochemistry and Western blot showed an increased level of p53, phosphorylated-p38MAPK and AQP4 and a reduced level of Kir4.1; all of which could be reversed following PFT-α treatment. Treble labeling staining revealed colocalization of p53 with phosphorylated-p38MAPK and unmatched expression of AQP4 and Kir4.1 within astrocyte cells.
  
  
  CONCLUSIONS
  These results indicated p53 mediates the formation of cytotoxic edema in the brain following SAH; an uncoupling expression of AQP4 and Kir4.1 on astrocytic end feet orchestrated by p38MAPK was partly responsible.
authors.affiliation: Department of Anatomy and Embryology, School of Basic Medical Sciences, Peking University, Beijing, China. yjh@bjmu.edu.cn
authors.forename: Jun-hao
authors.initials: JH
authors.lastname: Yan
authors.forename: Nikan H
authors.initials: NH
authors.lastname: Khatibi
authors.forename: Hong-bin
authors.initials: HB
authors.lastname: Han
authors.forename: Qin
authors.initials: Q
authors.lastname: Hu
authors.forename: Chun-hua
authors.initials: CH
authors.lastname: Chen
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Xiao-mei
authors.initials: XM
authors.lastname: Yang
authors.forename: Chang-man
authors.initials: CM
authors.lastname: Zhou
mesh_terms: D000818:Animals; D051401:Aquaporin 4 / Q000096:biosynthesis*; D052160:Benzothiazoles / Q000494:pharmacology; D001929:Brain Edema / Q000150:complications / Q000378:metabolism*; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D024661:Potassium Channels, Inwardly Rectifying / Q000096:biosynthesis* / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013345:Subarachnoid Hemorrhage / Q000150:complications / Q000378:metabolism*; D014050:Toluene / Q000031:analogs & derivatives / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics; D000098854:Kcnj10 Channel
chemical_list: C496032:Aqp4 protein, rat; D051401:Aquaporin 4; D052160:Benzothiazoles; D000098854:Kcnj10 Channel; D024661:Potassium Channels, Inwardly Rectifying; D016159:Tumor Suppressor Protein p53; D014050:Toluene; C121565:pifithrin