Hyponatremia

Astrocyte swelling represents the major factor responsible for the brain edema associated with fulminant hepatic failure (FHF). The edema may be of such magnitude as to increase intracranial pressure leading to brain herniation and death. Of the various agents implicated in the generation of astrocyte swelling, ammonia has had the greatest amount of experimental support. This article reviews mechanisms of ammonia neurotoxicity that contribute to astrocyte swelling. These include oxidative stress and the mitochondrial permeability transition (MPT). The involvement of glutamine in the production of cell swelling will be highlighted. Evidence will be provided that glutamine induces oxidative stress as well as the MPT, and that these events are critical in the development of astrocyte swelling in hyperammonemia.

Mechanisms of Ammonia-Induced Astrocyte Swelling

Alterations in cellular hydration not only contribute to metabolic regulation, but also critically determine the cellular response to different kinds of stress. Whereas cell swelling triggers anabolic pathways and protects cells from heat and oxidative challenge, cellular dehydration contributes to insulin resistance and catabolism and increases the cellular susceptibility to stress-induced damage. Intracellular accumulation of organic osmolytes, cell cycle delay and the expression of heat shock proteins provide cellular tolerance to hyperosmolarity and protect against stressors under dehydrating conditions. This article discusses some mechanisms by which alterations in cell hydration contribute to cytoprotection or cell damage. In addition, the close relationship between osmotic and oxidative stress and the contribution of isoosmotic shrinkage to apoptotic cell death are considered.

The cellular hydration state: a critical determinant for cell death and survival.

Hepatic encephalopathy (HE) defines a primary gliopathy associated with acute and chronic liver disease. Astrocyte swelling triggered by ammonia in synergism with different precipitating factors, including hyponatremia, tumor necrosis factor (TNF)-alpha, glutamate and ligands of the peripheral benzodiazepine receptor (PBR), is an early pathogenetic event in HE. On the other hand, reactive nitrogen and oxygen species (RNOS) including nitric oxide are considered to play a major role in HE. There is growing evidence that osmotic and oxidative stresses are closely interrelated. Astrocyte swelling produces RNOS and vice versa. Based on recent investigations, this review proposes a working model that integrates the pathogenetic action of osmotic and oxidative stresses in HE. Under participation of the N-methyl-D-aspartate (NMDA) receptor, Ca(2+), the PBR and organic osmolyte depletion, astrocyte swelling and RNOS production may constitute an autoamplificatory signaling loop that integrates at least some of the signals released by HE-precipitating factors.

Pathogenetic interplay between osmotic and oxidative stress: the hepatic encephalopathy paradigm.

Astrocyte swelling is observed in different types of brain injury. We studied a potential contribution of swelling to protein tyrosine nitration (PTN) by using cultured rat astrocytes exposed to hypoosmotic (205 mosmol/L) medium. Hypoosmolarity (2 h) increases total PTN by about 2-fold in 2 h. The hypoosmotic PTN is significantly inhibited by the NMDA receptor antagonist MK-801, the nitric oxide synthase (NOS) inhibitor L-NMMA, the extracellular Ca2+ chelator EGTA and the calmodulin antagonist W13, suggesting the involvement of NMDA receptor activation, influx of extracellular Ca2+ and Ca2+/calmodulin-dependent NO synthesis. Further, superoxide dismutase plus catalase and uric acid strongly inhibit hypoosmotic PTN, suggesting the involvement of the toxic metabolite peroxynitrite (ONOO−) as a nitrating agent. Hypoosmotic astrocyte swelling rapidly stimulates generation of reactive oxygen intermediates; this process is prevented by MK-801 and EGTA. In addition, MK-801 inhibits the hypoosmotic elevation of [Ca2+]i. The findings support the view that astrocyte swelling as induced, for example, by toxins relevant for hepatic encephalopathy is sufficient to produce oxidative stress and PTN and thus contributes to altered astroglial and neuronal function. © 2004 Wiley-Liss, Inc.

Hypoosmotic swelling increases protein tyrosine nitration in cultured rat astrocytes.

https://www.kidney-international.org/article/S0085-2538(15)59360-5/pdf

Edward C. Clark

Papers

Depletion of glutathione from brain cells in hyponatremia