Protein tyrosine nitration in hyperammonemia and hepatic encephalopathy.
Hepatic encephalopathy is seen as a clinical manifestation of a chronic low grade cerebral edema, which is thought to trigger disturbances of astrocyte function, glioneuronal communication, and finally HE symptoms. In cultured astrocytes, hypoosmotic swelling triggers a rapid oxidative stress response, which involves the action of NADPH oxidase isoenzymes, followed by tyrosine nitration of distinct astrocytic proteins. Oxidative stress and protein tyrosine nitration (PTN) are also observed in response to ammonia, inflammatory cytokines, such as TNF-alpha or interferons, and benzodiazepines with affinity to the peripheral benzodiazepine receptor (PBR). NMDA receptor activation was identified as upstream event in protein tyrosine nitration (PTN). Cerebral PTN is also found in vivo after administration of ammonia, benzodiazepines or lipopolysaccharide and in portocaval shunted rats. PTN predominantly affects astrocytes surrounding cerebral vessels with potential impact on blood-brain-barrier permeability. Among the tyrosine-nitrated proteins, glutamine synthetase, GAPDH, extracellular signal-regulated kinase and the PBR were identified. PTN of glutamine synthetase is associated with inactivation of the enzyme. Thus, factors known to trigger hepatic encephalopathy induce oxidative/nitrosative stress on astrocytes with protein modifications through PTN. The pathobiochemical relevance of astrocytic PTN for the development of HE symptoms remains to be established.
Häussinger
Dieter
D
Clinic for Gastroenterology, Hepatology and Infectiology, Heinrich-Heine-University Düsseldorf, D-40225, Düsseldorf, Germany.
Görg
Boris
B
Reinehr
Roland
R
Schliess
Freimut
F
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology; D006501:Hepatic Encephalopathy / Q000378:metabolism*; D006801:Humans; D022124:Hyperammonemia / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009566:Nitrates / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism*
D009419:Nerve Tissue Proteins; D009566:Nitrates; D016194:Receptors, N-Methyl-D-Aspartate; D014443:Tyrosine