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Down‐regulation of Kir4.1 in the cerebral cortex of rats with liver failure and in cultured astrocytes treated with glutamine: Implications for astrocytic dysfunction in hepatic encephalopathy
Author(s) -
ObaraMichlewska Marta,
Pannicke Thomas,
Karl Anett,
Bringmann Andreas,
Reichenbach Andreas,
Szeliga Monika,
Hilgier Wojciech,
Wrzosek Antoni,
Szewczyk Adam,
Albrecht Jan
Publication year - 2011
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.22656
Subject(s) - thioacetamide , glutamine , astrocyte , cerebral cortex , glutamine synthetase , hepatic encephalopathy , medicine , endocrinology , cerebral edema , biology , glutamate receptor , efflux , chemistry , biochemistry , central nervous system , amino acid , cirrhosis , receptor
Brain edema in acute hepatic encephalopathy (HE) is due mainly to swelling of astrocytes. Efflux of potassium is implicated in the prevention of glial swelling under hypoosmotic conditions. We investigated whether pathogenic factors of HE, glutamine (Gln) and/or ammonia, induce alterations in the expression of glial potassium channels (Kir4.1, Kir2.1) and Na + ‐K + ‐2Cl − cotransporter‐1 (NKCC1) in rat cerebral cortex and cultured rat cortical astrocytes and whether these alterations have consequences for potassium efflux and astrocytic swelling. Thioacetamide‐induced acute liver failure in rats resulted in significant decreases in the Kir4.1 mRNA and protein contents of cerebral cortex, whereas expression of Kir2.1 and NKCC1 remained unaltered. Incubation of primary cortical astrocytes for 72 hr in the presence of Gln (5 mM), but not of ammonia (5 mM or 10 mM), induced a decrease in the levels of Kir4.1 mRNA and protein. Similarly to incubation with Gln, reduction of Kir4.1 mRNA expression by RNA interference caused swelling of astrocytes as shown by confocal imaging followed by 3D computational analysis. Gln reduced the astrocytic uptake of D‐[ 3 H]aspartate, but, in contrast to the earlier reported effect of ammonia, this reduction was not accompanied by decreased expression of the astrocytic glutamate transporter GLT‐1 mRNA. Both Gln and ammonia decreased hypoosmolarity‐induced 86 Rb efflux from the cells, but the effect was more pronounced with Gln. The results indicate that down‐regulation of Kir4.1 may mediate distinct aspects of Gln‐induced astrocytic dysfunction in HE. © 2011 Wiley‐Liss, Inc.