期刊
GLIA
卷 56, 期 4, 页码 365-377出版社
WILEY
DOI: 10.1002/glia.20624
关键词
green fluorescent protein; cell sorting; ammonia; brain edema; connexin 43; aquaporin 4; Kir4.1; Kir5.1
资金
- NCRR NIH HHS [U54 RR019453, 5U54RR019453] Funding Source: Medline
- NICHD NIH HHS [P30HD40677, R24 HD050846, P30 HD040677, R24HD050846] Funding Source: Medline
- NINDS NIH HHS [R21NS050463, R21 NS050463] Funding Source: Medline
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 FAGS 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, NH4+ 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. (c) 2008 Wiley-Liss, Inc.
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