title: Expression of astrocytic genes coding for proteins implicated in neural excitation and brain edema is altered after acute liver failure.
abstract: In vitro and in vivo studies have suggested that reduced astrocytic uptake of neuronally released glutamate, alterations in expression of glial fibrillary acidic protein (GFAP) and aquaporin-4 (AQP-4) contribute to brain edema in acute liver failure (ALF). However, there is no evidence to date to suggest that these alterations occur in patients with ALF. We analyzed the mRNA expression of excitatory amino acid transporters (EAAT-1, EAAT-2), GFAP, and AQP-4 in the cerebral cortex obtained at autopsy from eight patients with ALF and from seven patients with no evidence of hepatic or neurological disorders by real-time PCR, and protein expression was assessed using immunoblotting and immunohistochemistry. We demonstrated a significant decrease in GFAP mRNA and protein levels in ALF patients compared to controls. While the loss of EAAT-2 protein in ALF samples was post-translational in nature, EAAT-1 protein remained within normal limits. Immunohistochemistry confirmed that, in all cases, the losses of EAAT-2 and GFAP were uniquely astrocytic in their localization. AQP-4 mRNA expression was significantly increased and its immunohistochemistry demonstrated increased AQP-4 immunoreactivity in the glial end-feet process surrounding the microvessels. These findings provide evidence of selective alterations in the expression of genes coding for key astrocytic proteins implicated in central nervous system (CNS) excitability and brain edema in human ALF. We investigated the gene expression of astrocytic proteins involved in astrocyte swelling causing brain edema in autopsied brain tissues of patients with acute liver failure. This study demonstrated loss of GFAP expression and up-regulation of AQP-4 protein expression leading to cerebral edema, and loss of EAAT-2 expression implicated in excitatory neurotransmission. These findings may provide new drug targets against CNS complications of acute liver failure.
authors.affiliation: Department of Hepatology, Postgraduate Institute of Medical Education & Research, Chandigarh, India.
authors.forename: Kiran K
authors.initials: KK
authors.lastname: Thumburu
authors.forename: Radha K
authors.initials: RK
authors.lastname: Dhiman
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Vasishta
authors.forename: Anuradha
authors.initials: A
authors.lastname: Chakraborti
authors.forename: Roger F
authors.initials: RF
authors.lastname: Butterworth
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Beauchesne
authors.forename: Paul
authors.initials: P
authors.lastname: Desjardins
authors.forename: Sandeep
authors.initials: S
authors.lastname: Goyal
authors.forename: Navneet
authors.initials: N
authors.lastname: Sharma
authors.forename: Ajay
authors.initials: A
authors.lastname: Duseja
authors.forename: Yogesh
authors.initials: Y
authors.lastname: Chawla
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D051401:Aquaporin 4 / Q000378:metabolism; D001253:Astrocytes / Q000378:metabolism*; D015153:Blotting, Western; D001929:Brain Edema / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D027341:Excitatory Amino Acid Transporter 1 / Q000096:biosynthesis / Q000235:genetics; D027342:Excitatory Amino Acid Transporter 2; D005260:Female; D015870:Gene Expression / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D050491:Glutamate Plasma Membrane Transport Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D017114:Liver Failure, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009474:Neurons / Q000502:physiology*; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D055815:Young Adult
chemical_list: D051401:Aquaporin 4; D018076:DNA, Complementary; D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2; D005904:Glial Fibrillary Acidic Protein; D050491:Glutamate Plasma Membrane Transport Proteins; D012333:RNA, Messenger; C493397:SLC1A2 protein, human; C493394:SLC1A3 protein, human; D012313:RNA
keywords: EAAT-1; EAAT-2; GFAP; acute liver failure; aquaporin-4; astrocyte protein; brain edema