[Effects of urantide, a urotensin receptor inhibitor, on acute hepatocyte apoptosis in mice].

Abstract

OBJECTIVE:

To explore the effects of urantide, a urotensin II receptor (UT) inhibitor, on lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced acute hepatocyte apoptosis in mice.

METHODS:

Male BALB/c mice were randomly divided into 4 groups (n = 6 each): normal control, pre-treatment control, model and pre-treatment model. The pre-treatment control and pre-treatment model groups received urantide (0.6 mg/kg body weight) by a caudal vein injection. At 30 minutes post-injection, the model and pre-treatment model groups were treated with LPS/D-GalN to induce acute hepatocyte apoptosis via an intraperitoneal injection. Hepatocyte apoptosis was examined by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) and caspase-3 colorimetric assay. The expressions of proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-α), interferon-γ (IFN-γ) and interleukin-1 beta (IL-1β), were detected by reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay.

RESULTS:

Massive hepatocyte apoptosis were detected in the model group. The apoptotic index was clearly reduced in the pre-treatment model group [(26 ± 11)% vs (77 ± 20)%, P < 0.01]. And the activity of caspase-3 was also lower in the pre-treatment model group than that in the model group [(2.50 ± 0.83) pmol · min(-1) · mg(-1) vs (3.76 ± 0.42) pmol · min(-1) · mg(-1), P < 0.01]. In addition, the serum and liver tissue levels of TNF-α, IL-1β and IFN-γ in the pre-treatment model group were significantly lower than those in the model group[1.69 ± 0.47 vs 3.57 ± 0.79, 0.31 ± 0.02 vs 0.46 ± 0.06, 2.81 ± 0.72 vs 3.35 ± 0.84, (233 ± 36) pg/ml vs (441 ± 157) pg/ml, (228 ± 21) pg/ml vs (364 ± 20) pg/ml, (93.8 ± 5.2) pg/ml vs (180.3 ± 4.3) pg/ml, all P < 0.01].

CONCLUSION:

LPS/D-GalN-induced acute hepatocyte apoptosis can be inhibited by a pretreatment of urantide through an inhibition of expression and secretion of proinflammatory cytokines. The UII/UT receptor system plays a pivotal role in the liver immuno-inflammatory injury of acute liver failure (ALF). And it may become a new drug target of ALF therapy.

• Authors: Fang-ping Yu, Liang Zhao, Liang-ming Liu, Dong-yu Liang, Dao-hua Yang, Fang-fang Zhang, Chang-gen Ye
• Journal: Zhonghua yi xue za zhi (Zhonghua Yi Xue Za Zhi) Vol. 91 Issue 47 Pg. 3358-62 (Dec 20 2011) ISSN: 0376-2491 [Print] China
• PMID: 22333205 (Publication Type: English Abstract, Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Interleukin-1beta
• Peptide Fragments
• Receptors, G-Protein-Coupled
• Tumor Necrosis Factor-alpha
• Urotensins
• urotensin II (4-11), Pen(5)-Trp(7)-Orn(8)-
• urotensin II receptor, mouse
• Interferon-gamma
• Casp3 protein, mouse
• Caspase 3

Topics

• Animals
• Apoptosis (drug effects)
• Caspase 3 (metabolism)
• Hepatocytes (drug effects, metabolism, pathology)
• Interferon-gamma (metabolism)
• Interleukin-1beta (metabolism)
• Liver Failure, Acute (chemically induced, pathology)
• Male
• Mice
• Mice, Inbred BALB C
• Peptide Fragments (pharmacology)
• Receptors, G-Protein-Coupled (antagonists & inhibitors)
• Tumor Necrosis Factor-alpha (metabolism)
• Urotensins (pharmacology)