Abstract
BackgroundAngiotensinogen is the precursor of angiotensin II, which is associated with ischemia-reperfusion injury. Angiotensin II reduces liver regeneration after hepatectomy and causes dysfunction and failure of reduced-size liver transplants. However, the regulation of angiotensinogen during liver regeneration is still unclear.AimsTo investigate the regulation of angiotensinogen during liver regeneration for preventing angiotensin II-related ischemia-reperfusion injury during liver regeneration.MethodsA mouse in vitro partial hepatectomy animal model was used to evaluate the expression of interleukin-6 (IL-6) and angiotensinogen during liver regeneration. Serum IL-6 and angiotensinogen were detected by enzyme immunoassay (EIA). Angiotensinogen mRNA was detected by RT-PCR. Tissue levels of angiotensinogen protein were detected by Western blot analysis. Primary cultures of mouse hepatocytes were used to investigate IL-6-induced angiotensinogen. Chemical inhibitors were used to perturb signal transduction pathways. Synthetic double-stranded oligodeoxynucleotides (ODNs) were used as ‘decoy’ cis-elements to investigate transcription. Ki 67 staining and quantification were used to verify liver regeneration.ResultsIn the in vivo model, the levels of serum IL-6 and angiotensinogen correlated. In the in vitro model, IL-6 transcriptionally regulated angiotensinogen expression. Additionally, IL-6 mediated angiotensinogen expression through the Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) and JAK/p38 signaling. Decoy ODN analyses revealed that STAT3 and nuclear factor-kB (NF-kB) also played critical roles in the transcriptional regulation of angiotensinogen by IL-6. IL-6-mediated signaling, JAK2, STAT3 and p38 inhibitors reduced angiotensinogen expression in the partially hepatectomized mice.ConclusionDuring liver regeneration, IL-6-enhanced angiotensinogen expression is dependent on the JAK/STAT3 and JAK/p38/NF-kB signaling pathways. Interruption of the molecular mechanisms of angiotensinogen regulation may be applied as the basis of therapeutic strategies for preventing angiotensin II-related ischemia-reperfusion injury during liver regeneration.
Highlights
Liver regeneration occurs after a loss of liver mass or liver injury, such as that resulting from the resection of liver tumors or trauma repair [1,2]
Decoy ODN analyses revealed that signal transducer and activator of transcription 3 (STAT3) and nuclear factor-kB (NF-kB) played critical roles in the transcriptional regulation of angiotensinogen by IL-6
During liver regeneration, IL-6-enhanced angiotensinogen expression is dependent on the Janus kinase (JAK)/STAT3 and JAK/ p38/NF-kB signaling pathways
Summary
Liver regeneration occurs after a loss of liver mass or liver injury, such as that resulting from the resection of liver tumors or trauma repair [1,2]. Liver regeneration is widely studied by mimicking such clinical conditions via partial hepatectomy in rodents. The reproducibility of partial hepatectomy has made it the preferred approach for studies of liver regeneration. Angiogenesis, an important process for tissue growth, is essential for liver regeneration [5]. Several factors are involved in angiogenesis including plasminogen, vascular endothelial growth factor, and vascular endothelial cells [6,7,8]. The regulation of apoptosis is important during liver regeneration [9,10], and there is a fine balance between cell proliferation and apoptosis. IL-6 plays a crucial role in regulating the regeneration of hepatocytes after hepatitis or partial hepatectomy [12]. The regulation of angiotensinogen during liver regeneration is still unclear
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