Ammonia induces RNA oxidation in cultured astrocytes and brain<i>in vivo</i>

Görg, Boris; Qvartskhava, Natalia; Keitel, Verena; Bidmon, Hans‐Jürgen; Selbach, Oliver; Schliess, Freimut; Häussinger, Dieter

doi:10.1002/hep.22345

Cited by 129 publications

(120 citation statements)

References 39 publications

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“…Ammonia intoxication and HE were shown to trigger PTN nitration and RNA oxidation in the rat and human brain, respectively (10,17,21,29). Therefore, we analyzed whether these effects could also be observed in brain tissue from liver-specific GS KO mice.…”

Section: Resultsmentioning

confidence: 99%

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Hyperammonemia in gene-targeted mice lacking functional hepatic glutamine synthetase

Qvartskhava

Lang

Görg

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Urea cycle defects and acute or chronic liver failure are linked to systemic hyperammonemia and often result in cerebral dysfunction and encephalopathy. Although an important role of the liver in ammonia metabolism is widely accepted, the role of ammonia metabolizing pathways in the liver for maintenance of whole-body ammonia homeostasis in vivo remains ill-defined. Here, we show by generation of liver-specific Gln synthetase (GS)-deficient mice that GS in the liver is critically involved in systemic ammonia homeostasis in vivo. Hepatic deletion of GS triggered systemic hyperammonemia, which was associated with cerebral oxidative stress as indicated by increased levels of oxidized RNA and enhanced protein Tyr nitration. Liver-specific GS-deficient mice showed increased locomotion, impaired fear memory, and a slightly reduced life span. In conclusion, the present observations highlight the importance of hepatic GS for maintenance of ammonia homeostasis and establish the liver-specific GS KO mouse as a model with which to study effects of chronic hyperammonemia.hepatic encephalopathy | metabolic zonation | oxidative stress | RNA oxidation | glutamine

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Section: Resultsmentioning

confidence: 99%

“…Northwestern blot analysis was carried out as described in SI Materials and Methods and previously (10).…”

Section: Methodsmentioning

confidence: 99%

Hyperammonemia in gene-targeted mice lacking functional hepatic glutamine synthetase

Qvartskhava

Lang

Görg

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…It has been shown that ammonia applied to cultured astrocytes, at concentrations of 100 and 200 μM, does not induce oxidative stress, while concentrations of ammonia >500 μM result in ROS generation (Görg et al, 2008 andMehrotra andTrigun, 2012). In vivo, blood and brain ammonia levels are significantly lower in CLD rats than in ALF (<250 μM in CLD compared to >800 μM in ALF, ( Bosoi et al, 2012 andJiang et al, 2009c)); however, cerebral oxidative stress was observed only in ALF rats.…”

Section: Oxidative Stressmentioning

confidence: 99%

Brain edema in acute liver failure and chronic liver disease: Similarities and differences

Bosoi

Rose

2013

Neurochemistry International

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Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome that typically develops as a result of acute liver failure or chronic liver disease. Brain edema is a common feature associated with HE. In acute liver failure, brain edema contributes to an increase in intracranial pressure, which can fatally lead to brain stem herniation. In chronic liver disease, intracranial hypertension is rarely observed, even though brain edema may be present. This discrepancy in the development of intracranial hypertension in acute liver failure versus chronic liver disease suggests that brain edema plays a different role in relation to the onset of HE. Furthermore, the pathophysiological mechanisms involved in the development of brain edema in acute liver failure and chronic liver disease are dissimilar. This review explores the types of brain edema, the cells, and pathogenic factors involved in its development, while emphasizing the differences in acute liver failure versus chronic liver disease. The implications of brain edema developing as a neuropathological consequence of HE, or as a cause of HE, are also discussed. HighlightsBrain edema is a common feature in ALF and CLD. HE is inconsistently associated with the presence of brain edema. Fibrous and protoplasmic astrocytes are differentially implicated in the pathogenesis of HE. The pathogenesis of HE is multifactorial causing an array of neurological symptoms.

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“…In line with this possibility, it has been demonstrated that RNA is a target for oxidation during acute HE (Görg et al, 2008). These authors observed that 7% of total RNA was oxidized in cultures of astrocytes Fig.…”

Section: Discussionmentioning

confidence: 67%

“…exposed to 1 mM ammonia, while 6% of total RNA was found oxidized in cerebral cortex of hyperammonemic rats (Görg et al, 2008). Oxidized mRNA has been related to abnormal protein level and function (Nunomura et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Expression of glutamine transporter isoforms in cerebral cortex of rats with chronic hepatic encephalopathy

Leke

Escobar

Rao

et al. 2015

Neurochemistry International

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Rama Rao, Kakulavarapu V.; Silveira, Themis Reverbel; Norenberg, Michael D.; and Schousboe, Arne, "Expression of glutamine transporter isoforms in cerebral cortex of rats with chronic hepatic encephalopathy" (2015 Keywords:Chronic hepatic encephalopathy Glutamine transporters Glutamine GABA A B S T R A C THepatic encephalopathy (HE) is a neuropsychiatric disorder that occurs due to acute and chronic liver diseases, the hallmark of which is the increased levels of ammonia and subsequent alterations in glutamine synthesis, i.e. conditions associated with the pathophysiology of HE. Under physiological conditions, glutamine is fundamental for replenishment of the neurotransmitter pools of glutamate and GABA. The different isoforms of glutamine transporters play an important role in the transfer of this amino acid between astrocytes and neurons. A disturbance in the GABA biosynthetic pathways has been described in bile duct ligated (BDL) rats, a well characterized model of chronic HE. Considering that glutamine is important for GABA biosynthesis, altered glutamine transport and the subsequent glutamate/GABA-glutamine cycle efficacy might influence these pathways. Given this potential outcome, the aim of the present study was to investigate whether the expression of the glutamine transporters SAT1, SAT2, SN1 and SN2 would be affected in chronic HE. We verified that mRNA expression of the neuronal glutamine transporters SAT1 and SAT2 was found unaltered in the cerebral cortex of BDL rats. Similarly, no changes were found in the mRNA level for the astrocytic transporter SN1, whereas the gene expression of SN2 was increased by two-fold in animals with chronic HE. However, SN2 protein immuno-reactivity did not correspond with the increase in gene transcription since it remained unaltered. These data indicate that the expression of the glutamine transporter isoforms is unchanged during chronic HE, and thus likely not to participate in the pathological mechanisms related to the imbalance in the GABAergic neurotransmitter system observed in this neurologic condition.

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Ammonia induces RNA oxidation in cultured astrocytes and brainin vivo

Cited by 129 publications

References 39 publications

Hyperammonemia in gene-targeted mice lacking functional hepatic glutamine synthetase

Hyperammonemia in gene-targeted mice lacking functional hepatic glutamine synthetase

Brain edema in acute liver failure and chronic liver disease: Similarities and differences

Expression of glutamine transporter isoforms in cerebral cortex of rats with chronic hepatic encephalopathy

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