Ammonia is a major player in the pathogenesis of hepatic encephalopathy (HE) and affects astrocyte function by triggering a self-amplifying cycle between osmotic and oxidative stress. We recently demonstrated that hypoosmotic astrocyte swelling rapidly stimulates nitric oxide (NO) production and increases intracellular free Zn 2+ concentration ((Zn 2+ ) i ). Here we report effects of ammonia on (Zn 2+ ) i homeostasis and NO synthesis. In cultured rat astrocytes, NH 4 Cl (5 m m ) increased within 6 h both cytosolic and mitochondrial (Zn 2+ ). The (Zn 2+ ) i increase was transient and was mimicked by the nonmetabolizable CH 3 NH 3 Cl, and it was dependent on NO formation, as evidenced by the sensitivity toward the nitric oxide synthase inhibitor N G -monomethyl- l -arginine. The NH 4 Cl-induced NO formation was sensitive to the Ca 2+ chelator 1,2- bis ( o -aminophenoxy)ethane- N , N , N ′, N ′-tetraacetic acid tetra(acetoxymethyl) ester and increases in both NO and (Zn 2+ ) i were blocked by the N -methyl- d -aspartate receptor antagonist MK-801. The NH 4 Cl-triggered increase in (Zn 2+ ) i was followed by a Zn 2+ -dependent nuclear appearance of the metal response element-binding transcription factor and metallothionein messenger RNA (mRNA) induction. Metallothionein mRNA was also increased in vivo in rat cerebral cortex 6 h after an NH 4 Ac challenge. NH 4 Cl increased peripheral-type benzodiazepine receptor (PBR) protein expression, whereas PBR mRNA levels were decreased in a Zn 2+ -independent manner. The Zn 2+ -dependent upregulation of metallothionein following ammonia intoxication may reflect a cytoprotective response, whereas the increase in PBR expression may augment HE development.
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Ammonia increases nitric oxide, free Zn 2+ , and metallothionein mRNA expression in cultured rat astrocytes
Kruczek, Carolin; Görg, Boris; Keitel, Verena; Bidmon, Hans J.; Schliess, Freimut; Häussinger, Dieter
Follow Biological Chemistry
, Volume 392 (12)
de Gruyter – Dec 1, 2011
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