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Gene expression profiling of astrocytes from hyperammonemic mice reveals altered pathways for water and potassium homeostasis in vivo
Author(s) -
LichterKonecki Uta,
Mangin Jean Marie,
Gordishdressman Heather,
Hoffman Eric P.,
Gallo Vittorio
Publication year - 2008
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.20624
Subject(s) - biology , homeostasis , in vivo , gene expression profiling , gene expression , neuroscience , microbiology and biotechnology , potassium , astrocyte , gene , central nervous system , genetics , chemistry , organic chemistry
Acute hyperammonemia (HA) causes cerebral edema and brain damage in children with urea cycle disorders (UCDs) and in patients in acute liver failure. Chronic HA is associated with developmental delay and mental retardation in children with UCDs, and with neuropsychiatric symptoms in patients with chronic liver failure. Astrocytes are a major cellular target of hyperammonemic encephalopathy, and changes occurring in these cells are thought to be causally related to the brain edema of acute HA. To study the effect of HA on astrocytes in vivo , we crossed the Otc spf mouse, a mouse with the X‐linked UCD ornithine transcarbamylase (OTC) deficiency, with the hGFAP‐EGFP mouse, a mouse selectively expressing green fluorescent protein in astrocytes. We used FACS to purify astrocytes from the brains of hyperammonemic and healthy Otc spf /GFAP‐EGFP mice. RNA isolated from these astrocytes was used in microarray expression analyses and qRT‐PCR. When compared with healthy littermates, we observed a significant downregulation of the gap‐junction channel connexin 43 ( Cx43 ) the water channel aquaporin 4 ( Aqp4 ) genes, and the astrocytic inward‐rectifying potassium channel (Kir) genes Kir4.1 and Kir5.1 in hyperammonemic mice. Aqp4, Cx43, and Kir4.1/Kir5.1 are co‐localized to astrocytic end‐feet at the brain vasculature, where they regulate potassium and water transport. Since, NH 4 + ions can permeate water and K + ‐channels, downregulation of these three channels may be a direct effect of elevated blood ammonia levels. Our results suggest that alterations in astrocyte‐mediated water and potassium homeostasis in brain may be key to the development of the brain edema. © 2008 Wiley‐Liss, Inc.