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Cited by 36Liver physiology and pathologyRenin-Angiotensin System StudiesOrgan Transplantation Techniques and Outcomes

Interleukin-6 Mediates Angiotensinogen Gene Expression during Liver Regeneration

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Lai, Hong-Shiee, Lin, Wen-Hsi, Lai, Shuo-Lun, Lin, Hao-Yu, Hsu, Wen-Ming, Chou, Chia-Hung, Lee, Po-Huang·2013·PLoS ONE
DOI 10.1371/journal.pone.0067868PMC PMC3700864
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Abstract

BACKGROUND: Angiotensinogen 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. AIMS: To investigate the regulation of angiotensinogen during liver regeneration for preventing angiotensin II-related ischemia-reperfusion injury during liver regeneration. METHODS: A 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. RESULTS: In 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. CONCLUSION: During 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.

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Cited by

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Authors
Lai, H.-S., Lin, W.-H., Lai, S.-L., Lin, H.-Y., Hsu, W.-M., Chou, C.-H., & Lee, P.-H.
Affiliations
National Taiwan University (TW)
Corresponding author
Lai, Hong-Shiee
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2013-07-03
Volume
8
Issue
7
Pages
e67868
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0067868
PMC
PMC3700864
OpenAlex
W2026965993
Cited by
36
References
2
Citations by year
2025: 3 · 2024: 3 · 2022: 4 · 2021: 3 · 2020: 5 · 2019: 2 · 2018: 4 · 2017: 2 · 2016: 5 · 2015: 3 · 2014: 2
FWCI
2.08
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Science Council (NSC 100)
  • National Taiwan University Hospital
  • National Taiwan University
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
  • Health Sciences › Medicine › Surgery › Organ Transplantation Techniques and Outcomes
Keywords
interleukin-6, angiotensinogen, liver regeneration, partial hepatectomy, angiotensin II, ischemia-reperfusion injury, JAK/STAT3 signaling, p38 MAPK, NF-kB, transcriptional regulation, hepatocytes, decoy oligonucleotides
MeSH terms
Angiotensinogen, Animals, Gene Expression Regulation, Hepatectomy, Liver Regeneration, Male, Signal Transduction, Interleukin-6, NF-kappa B, Hepatocytes, p38 Mitogen-Activated Protein Kinases, STAT3 Transcription Factor, Mice, Janus Kinases

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