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Gene expression profiling of astrocytes from hyperammonemic mice reveals altered pathways for water and potassium homeostasis in vivo.
Glia. 2008 Mar; 56(4):365-77.GLIA

Abstract

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 Otcspf/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.

Authors+Show Affiliations

Center for Neuroscience Research, Children's National Medical Center, Washington, DC 20010, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18186079

Citation

Lichter-Konecki, Uta, et al. "Gene Expression Profiling of Astrocytes From Hyperammonemic Mice Reveals Altered Pathways for Water and Potassium Homeostasis in Vivo." Glia, vol. 56, no. 4, 2008, pp. 365-77.
Lichter-Konecki U, Mangin JM, Gordish-Dressman H, et al. Gene expression profiling of astrocytes from hyperammonemic mice reveals altered pathways for water and potassium homeostasis in vivo. Glia. 2008;56(4):365-77.
Lichter-Konecki, U., Mangin, J. M., Gordish-Dressman, H., Hoffman, E. P., & Gallo, V. (2008). Gene expression profiling of astrocytes from hyperammonemic mice reveals altered pathways for water and potassium homeostasis in vivo. Glia, 56(4), 365-77. https://doi.org/10.1002/glia.20624
Lichter-Konecki U, et al. Gene Expression Profiling of Astrocytes From Hyperammonemic Mice Reveals Altered Pathways for Water and Potassium Homeostasis in Vivo. Glia. 2008;56(4):365-77. PubMed PMID: 18186079.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Gene expression profiling of astrocytes from hyperammonemic mice reveals altered pathways for water and potassium homeostasis in vivo. AU - Lichter-Konecki,Uta, AU - Mangin,Jean Marie, AU - Gordish-Dressman,Heather, AU - Hoffman,Eric P, AU - Gallo,Vittorio, PY - 2008/1/11/pubmed PY - 2008/5/31/medline PY - 2008/1/11/entrez SP - 365 EP - 77 JF - Glia JO - Glia VL - 56 IS - 4 N2 - 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 Otcspf/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. SN - 0894-1491 UR - https://www.unboundmedicine.com/medline/citation/18186079/Gene_expression_profiling_of_astrocytes_from_hyperammonemic_mice_reveals_altered_pathways_for_water_and_potassium_homeostasis_in_vivo_ L2 - https://doi.org/10.1002/glia.20624 DB - PRIME DP - Unbound Medicine ER -