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Roles of changes in active glutamine transport in brain edema development during hepatic encephalopathy: an emerging concept.

Zielińska M, Popek M, Albrecht J - Neurochem. Res. (2013)

Bottom Line: Here we discuss the possibility that altered functioning of Gln transport proteins located in the cellular or mitochondrial membranes, modulates the effects of increased Gln synthesis.Studies on the expression of the cell membrane N-system transporters SN1 (SNAT3) and SN2 (SNAT5), which mediate Gln efflux from astrocytes rendered HE model-dependent effects.TAA-induced HE is also associated with decreased expression of mRNA coding for the system A carriers SAT1 and SAT2, which stimulate Gln influx to neurons.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawinskiego St. 5, 02-106, Warsaw, Poland, mzielinska@imdik.pan.pl.

ABSTRACT
Excessive glutamine (Gln) synthesis in ammonia-overloaded astrocytes contributes to astrocytic swelling and brain edema, the major complication of hepatic encephalopathy (HE). Much of the newly formed Gln is believed to enter mitochondria, where it is recycled to ammonia, which causes mitochondrial dysfunction (a "Trojan horse" mode of action). A portion of Gln may increase osmotic pressure in astrocytes and the interstitial space, directly and independently contributing to brain tissue swelling. Here we discuss the possibility that altered functioning of Gln transport proteins located in the cellular or mitochondrial membranes, modulates the effects of increased Gln synthesis. Accumulation of excess Gln in mitochondria involves a carrier-mediated transport which is activated by ammonia. Studies on the expression of the cell membrane N-system transporters SN1 (SNAT3) and SN2 (SNAT5), which mediate Gln efflux from astrocytes rendered HE model-dependent effects. HE lowered the expression of SN1 at the RNA and protein level in the cerebral cortex (cc) in the thioacetamide (TAA) model of HE and the effect paralleled induction of cerebral cortical edema. Neither SN1 nor SN2 expression was affected by simple hyperammonemia, which produces no cc edema. TAA-induced HE is also associated with decreased expression of mRNA coding for the system A carriers SAT1 and SAT2, which stimulate Gln influx to neurons. Taken together, changes in the expression of Gln transporters during HE appear to favor retention of Gln in astrocytes and/or the interstitial space of the brain. HE may also affect arginine (Arg)/Gln exchange across the astrocytic cell membrane due to changes in the expression of the hybrid Arg/Gln transporter y(+)LAT2. Gln export from brain across the blood-brain barrier may be stimulated by HE via its increased exchange with peripheral tryptophan.

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a, b Expression of SN1 and SN2 at the mRNA (a) and protein (b) level in cerebral cortex of control rats and rats with ammonium acetate-induced HA. Values in each group are mean ± SD for n = 4
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Fig3: a, b Expression of SN1 and SN2 at the mRNA (a) and protein (b) level in cerebral cortex of control rats and rats with ammonium acetate-induced HA. Values in each group are mean ± SD for n = 4

Mentions: Experiments carried out in this laboratory demonstrated a marked decrease of SN1 and SN2 expression at the mRNA and SN1 at the protein level, in the cc of rats with TAA-induced HE (Fig. 2a, b), coinciding with marked cc swelling in this model [40]. Interestingly, SN1 and SN2 expression remained unaltered in rats with simple hyperammonemia (HA) in the ammonium acetate model (Fig. 3a, b), where (cc) does not change its volume [40]. Two other groups have measured the effects of HE on SN2 mRNA expression in two different models. Our results are in agreement with decreased SN2 mRNA expression in the acute liver failure (azoxymethane) model in mice reported by Desjardins et al. [41]. The results of the present study are also compatible with the unchanged expression of SN2 protein in the mice TAA model similar to our model, as revealed immunocytochemically [42]. It must be reemphasized, however that, SN1 but not SN2 is believed to be the key mediator of the efflux of newly synthesized Gln from astrocytes [38].Fig. 2


Roles of changes in active glutamine transport in brain edema development during hepatic encephalopathy: an emerging concept.

Zielińska M, Popek M, Albrecht J - Neurochem. Res. (2013)

a, b Expression of SN1 and SN2 at the mRNA (a) and protein (b) level in cerebral cortex of control rats and rats with ammonium acetate-induced HA. Values in each group are mean ± SD for n = 4
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3926979&req=5

Fig3: a, b Expression of SN1 and SN2 at the mRNA (a) and protein (b) level in cerebral cortex of control rats and rats with ammonium acetate-induced HA. Values in each group are mean ± SD for n = 4
Mentions: Experiments carried out in this laboratory demonstrated a marked decrease of SN1 and SN2 expression at the mRNA and SN1 at the protein level, in the cc of rats with TAA-induced HE (Fig. 2a, b), coinciding with marked cc swelling in this model [40]. Interestingly, SN1 and SN2 expression remained unaltered in rats with simple hyperammonemia (HA) in the ammonium acetate model (Fig. 3a, b), where (cc) does not change its volume [40]. Two other groups have measured the effects of HE on SN2 mRNA expression in two different models. Our results are in agreement with decreased SN2 mRNA expression in the acute liver failure (azoxymethane) model in mice reported by Desjardins et al. [41]. The results of the present study are also compatible with the unchanged expression of SN2 protein in the mice TAA model similar to our model, as revealed immunocytochemically [42]. It must be reemphasized, however that, SN1 but not SN2 is believed to be the key mediator of the efflux of newly synthesized Gln from astrocytes [38].Fig. 2

Bottom Line: Here we discuss the possibility that altered functioning of Gln transport proteins located in the cellular or mitochondrial membranes, modulates the effects of increased Gln synthesis.Studies on the expression of the cell membrane N-system transporters SN1 (SNAT3) and SN2 (SNAT5), which mediate Gln efflux from astrocytes rendered HE model-dependent effects.TAA-induced HE is also associated with decreased expression of mRNA coding for the system A carriers SAT1 and SAT2, which stimulate Gln influx to neurons.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawinskiego St. 5, 02-106, Warsaw, Poland, mzielinska@imdik.pan.pl.

ABSTRACT
Excessive glutamine (Gln) synthesis in ammonia-overloaded astrocytes contributes to astrocytic swelling and brain edema, the major complication of hepatic encephalopathy (HE). Much of the newly formed Gln is believed to enter mitochondria, where it is recycled to ammonia, which causes mitochondrial dysfunction (a "Trojan horse" mode of action). A portion of Gln may increase osmotic pressure in astrocytes and the interstitial space, directly and independently contributing to brain tissue swelling. Here we discuss the possibility that altered functioning of Gln transport proteins located in the cellular or mitochondrial membranes, modulates the effects of increased Gln synthesis. Accumulation of excess Gln in mitochondria involves a carrier-mediated transport which is activated by ammonia. Studies on the expression of the cell membrane N-system transporters SN1 (SNAT3) and SN2 (SNAT5), which mediate Gln efflux from astrocytes rendered HE model-dependent effects. HE lowered the expression of SN1 at the RNA and protein level in the cerebral cortex (cc) in the thioacetamide (TAA) model of HE and the effect paralleled induction of cerebral cortical edema. Neither SN1 nor SN2 expression was affected by simple hyperammonemia, which produces no cc edema. TAA-induced HE is also associated with decreased expression of mRNA coding for the system A carriers SAT1 and SAT2, which stimulate Gln influx to neurons. Taken together, changes in the expression of Gln transporters during HE appear to favor retention of Gln in astrocytes and/or the interstitial space of the brain. HE may also affect arginine (Arg)/Gln exchange across the astrocytic cell membrane due to changes in the expression of the hybrid Arg/Gln transporter y(+)LAT2. Gln export from brain across the blood-brain barrier may be stimulated by HE via its increased exchange with peripheral tryptophan.

Show MeSH
Related in: MedlinePlus