Key result
Urantide pretreatment in LPS-stimulated Kupffer cells downregulated LC3 and p62 mRNA and LC3 II protein, upregulated p62 protein, inhibited Bcl-2, and increased cleaved caspase-3.
Why the study?
Although the UII/UT system mediates hepatic immune inflamed injury in acute liver failure with autophagy inhibition, whether it affects liver autophagy remained unknown.
Does pretreatment with UT receptor specific antagonist urantide alter autophagy and apoptosis pathways in LPS/D-GalN-induced acute liver failure models?
Does pretreatment with UT receptor specific antagonist urantide alter autophagy and apoptosis pathways in LPS/D-GalN-induced acute liver failure models?
Liver injury mediated by the UII/UT system in acute liver failure is likely associated with the activation of autophagy-related and apoptosis-resisted pathways in Kupffer cells.
Answers are grounded in this paper and cite their sources.
Hypothesis-generating in rodent Kupffer cells; leaves open any therapeutic role for urantide in human acute liver failure.
The system of urotensin II (UII) and its receptor (UT) (or: UII/UT system) mediates hepatic immune inflamed injury in acute liver failure (ALF) with autophagy inhibition. However, it is unknown whether the system has an effect on liver autophagy in ALF. In this study, we attempted to explore hepatic autophagy response in ALF through blocking the UII/UT signal. Autophagy-related genes were examined in the liver tissues of lipopolysaccharide (LPS)/d-galactosamine (D-GalN)-induced ALF after pretreatment of UT receptor specific antagonist urantide. And then, the levels of autophagy- and apoptosis-related genes were assayed in LPS-stimulated KCs via urantide pretreatment. We found that the expressions of hepatic autophagy related genes, including Beclin-1, Atg5, Atg7, LC3 and p62 mRNA, and LC3 II and p62 protein, were significantly downregulated in LPS/D-GalN-induced ALF mice; but they were not affected by pretreatment of urantide, a special UT receptor antagonist. To probe inflammatory mechanisms of the UII/UT system, we further investigated the effect of the system on Kupffer cells (KCs), the innate immune cells in liver. We found that urantide pretreatment significantly inhibited production of inflammatory injury molecules including TRAF6 and ROS in LPS-stimulated KCs. LPS stimulation induced LC3 and p62 mRNA and LC3 II and p62 protein expression in KCs. After urantide pretreatment, LC3 and p62 mRNA and LC3 II protein were downregulated, while p62 protein was upregulated in LPS-stimulated KCs. In addition, antiapoptotic protein Bcl-2 inhibition and proapoptotic protein cleaved caspase-3 increase were observed in LPS-stimulated KCs, and the effects were enhanced after urantide pretreatment in the study. We conclude that liver injury mediated by the UII/UT system is possibly associated with the activation of autophagy-related and apoptosis-resisted pathways of KCs in ALF.
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Zhong et al. (2021) studied Acute liver failure. Urantide (UT receptor specific antagonist) vs. LPS/D-GalN or LPS alone was evaluated on Expression of hepatic autophagy-related and apoptosis-related genes. Urantide pretreatment in LPS-stimulated Kupffer cells downregulated LC3 and p62 mRNA and LC3 II protein, upregulated p62 protein, inhibited Bcl-2, and increased cleaved caspase-3.
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