Abstract
BackgroundNumerous pathological processes that affect liver function in patients with liver failure have been identified. Among them, hyperammonia is one of the most common phenomena.The purpose of this study was to determine whether hyperammonia could induced specific liver injury.MethodsHyperammonemic cells were established using NH4Cl. The cells were assessed by MTT, ELISA, and flow cytometric analyses. The expression levels of selected genes and proteins were confirmed by quantitative RT-PCR and western blot analyses.ResultsThe effects of 20 mM NH4Cl pretreatment on the cell proliferation and apoptosis of primary hepatocytes and other cells were performed by MTT assays and flow cytometric analyses. Significant increasing in cytotoxicity and apoptosis were only observed in hepatocytes. The cell damage was reduced after adding BAPTA-AM but unchanged after adding EGTA. The expression levels of caspase-3, cytochrome C, calmodulin, and inducible nitric oxide synthase were increased and that of bcl-2 was reduced. The Na+-K+-ATPase activities in hyperammonia liver cells was no signiaficant difference compaired with the control group, but was decreased in astrocytes. NH4Cl pretreatment of primary hepatocytes promoted the activation of mitochondrial permeability transition pores and the mitochondria swelled irregularly.ConclusionsHyperammonia induces specific liver injury through an intrinsic Ca2+-independent apoptosis pathway.
Highlights
Numerous pathological processes that affect liver function in patients with liver failure have been identified
We found that NH4Cl induced specific liver injury compared with other cell types and apoptosis of primary hepatocytes was significantly increased compared with control cells
A dramatic time-dependent loss was found in cell viability when exposure to 20 mM and 50 mM ammonia, the viability of cells recovered when exposed to 5 mM ammonia for 48 h (Figure 2B)
Summary
Numerous pathological processes that affect liver function in patients with liver failure have been identified. Recent studies showed that increasing ammonia concentrations had deleterious effects on the functions of the central nervous system and the elevation of arterial ammonia was associated with high mortality in patients with acute liver failure [10,11]. Hyperammonia following acute and chronic liver diseases may lead to HE, which is accompanied by the failure of energy metabolism [13], disturbances of neurotransmission in the brain, and changes in Na+-K+-ATPase [14,15]. We hypothesized that hyperammonia might directly induce a series of changes leading to liver injury. To verify this assumption, a hyperammonia cell model was established to investigate the effects of NH4Cl on liver damage and further examine the effects of NH4Cl on hepatocyte apoptosis
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