Hepatic injury is associated with cell cycle arrest and apoptosis with alteration of cyclin A and D1 in ammonium chloride‑induced hyperammonemic rats

Gao,Xiaojuan; Fan,Lei; Li,Hua; Li,Juan; Liu,Xiaorui; Sun,Ranran; Yu,Zujiang

doi:10.3892/etm.2015.2931

Hepatic injury is associated with cell cycle arrest and apoptosis with alteration of cyclin A and D1 in ammonium chloride‑induced hyperammonemic rats

Authors:
- Xiaojuan Gao
- Lei Fan
- Hua Li
- Juan Li
- Xiaorui Liu
- Ranran Sun
- Zujiang Yu
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Affiliations: Department of Infectious Diseases, The First Afﬁliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China, Department of Pharmacy, Children's Hospital of Zhengzhou City, Zhengzhou, Henan 450053, P.R. China
Published online on: December 11, 2015 https://doi.org/10.3892/etm.2015.2931
Pages: 427-434
Copyright: © Gao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Hyperammonemia is considered to be central to the pathophysiology of hepatic encephalopathy in patients exhibiting hepatic failure (HF). It has previously been determined that hyperammonemia is a serious metabolic disorder commonly observed in patients with HF. However, it is unclear whether hyperammonemia has a direct adverse effect on hepatic cells or serves as a cause and effect of HF. The present study investigated whether hepatic injury is caused by hyperammonemia, and aimed to provide an insight into the causes and mechanisms of HF. Hyperammonemic rats were established via intragastric administration of ammonium chloride solution. Hepatic tissues were assessed using biochemistry, histology, immunohistochemistry, flow cytometry (FCM), semi‑quantitative reverse transcription‑polymerase chain reaction and western blot analysis. Hyperammonemic rats exhibited significantly increased levels of liver function markers, including alanine transaminase (P<0.01), aspartate aminotransferase (P<0.01), blood ammonia (P<0.01) and direct bilirubin (P<0.05), which indicated hepatic injury. A pathological assessment revealed mild hydropic degeneration, but no necrosis or inflammatory cell infiltration. However, terminal deoxynucleotidyl transferase dUTP nick end‑labeling assays confirmed a significant increase in the rate of cellular apoptosis in hyperammonemic rat livers (P<0.01). FCM analysis revealed that there were significantly more cells in the S phase and fewer in the G2/M phase (P<0.01), and the expression levels of cyclin A and D1 mRNA and proteins were significantly increased (P<0.01). In summary, cell cycle arrest, apoptosis and an alteration of cyclin A and D1 levels were all markers of hyperammonemia‑induced hepatic injury. These findings provide an insight into the potential mechanisms underlying hyperammonemia‑induced hepatic injury, and may be used as potential targets for treating or preventing hepatic damage caused by hyperammonemia, including hepatic encephalopathy.

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