Na-K-Cl Cotransporter-1 as a Regulator of Manganese-induced Astrocyte Swelling

Abstract

Astrocyte swelling leads to brain edema, intracranial pressure, brain herniation and acute liver failure (fulminant hepatic failure) which is the major cause of death in this condition. Manganese has been strongly implicated as an important factor in astrocyte swelling. Manganese in excess is neurotoxic and causes a CNS disorder that resembles  Parkinson¡¦s disease (manganism). Manganese highly accumulates in astrocytes, which renders these cells more vulnerable to its toxicity. In addition to manganism, increased brain levels of manganese have been found in hepatic encephalopathy. Manganese is known to cause cell
swelling in cultured astrocytes, although the means by which this occurs has not been fully elucidated. A disturbance in one or more of these systems may result in loss of ion homeostasis and cell swelling. In particular, activation of the Na-K-Cl cotransporter-1 (NKCC1) has been shown to be involved in cell swelling in several neurological disorders.
We therefore examined the effect of manganese on NKCC activity and its potential role in the swelling of astrocytes. Cultured astrocytes were exposed to manganese (50 µM), and NKCC activity was measured. Manganese increased NKCC activity at 24 h. Inhibition of this  activity by bumetanide diminished manganese-induced astrocyte swelling.  Manganese (Mn) also increased total as well as phosphorylated NKCC1. These results suggest that activation of NKCC1 is an important factor in the mediation of astrocyte swelling by manganese and that such activation appears to be mediated by NKCC1 abundance.