title: Blockade of the apelin-APJ system promotes mouse liver regeneration by activating Kupffer cells after partial hepatectomy.
abstract: BACKGROUND
  Liver regeneration after massive hepatectomy or living donor liver transplantation is critical. The apelin-APJ system is involved in the regulation of cardiovascular function, inflammation, fluid homeostasis, the adipo-insular axis, and angiogenesis, but its function in liver regeneration remains unclear.
  
  
  METHODS
  We investigated the impact of pharmacologic blockade of the apelin-APJ system, using the specific APJ antagonist F13A on liver regeneration after hepatectomy in mice.
  
  
  RESULTS
  F13A-treated mice had significantly higher serum concentrations of tumor necrosis factor (TNF)-α and interleukin (IL)-6 than control mice, due to F13A-promoted activation of Kupffer cells. Compared with untreated mice, F13A enhanced the signal transducer and activator of transcription 3 and mitogen-activated protein kinase pathways, stimulated cell-cycle progression, and promoted hepatocyte proliferation and liver regeneration without inducing apoptosis or inflammation in regenerating livers. In vitro, Kupffer cells expressed APJ and were activated directly by F13A treatment, releasing TNF-α and IL-6. Moreover, F13A-treated mice had a higher survival rate than untreated mice in the extended hepatectomy model.
  
  
  CONCLUSIONS
  F13A treatment promotes early phase liver regeneration after hepatectomy by promoting the activation of Kupffer cells and increasing serum levels of TNF-α and IL-6. F13A treatment may become a therapeutic option to facilitate efficient liver regeneration after liver surgery.
authors.affiliation: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan, yoshiya@surg2.med.kyushu-u.ac.jp.
authors.forename: Shohei
authors.initials: S
authors.lastname: Yoshiya
authors.forename: Ken
authors.initials: K
authors.lastname: Shirabe
authors.forename: Daisuke
authors.initials: D
authors.lastname: Imai
authors.forename: Takeo
authors.initials: T
authors.lastname: Toshima
authors.forename: Yo-ichi
authors.initials: Y
authors.lastname: Yamashita
authors.forename: Toru
authors.initials: T
authors.lastname: Ikegami
authors.forename: Shinji
authors.initials: S
authors.lastname: Okano
authors.forename: Tomoharu
authors.initials: T
authors.lastname: Yoshizumi
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Kawanaka
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Maehara
mesh_terms: D000818:Animals; D000075244:Apelin Receptors; D004195:Disease Models, Animal; D015536:Down-Regulation; D005786:Gene Expression Regulation; D006498:Hepatectomy; D022781:Hepatocytes / Q000378:metabolism*; D066298:In Vitro Techniques; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000494:pharmacology*; D015850:Interleukin-6 / Q000235:genetics; D007728:Kupffer Cells / Q000378:metabolism*; D008115:Liver Regeneration / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects* / Q000235:genetics; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D000075244:Apelin Receptors; C491285:Aplnr protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6; D043562:Receptors, G-Protein-Coupled; D014409:Tumor Necrosis Factor-alpha; C532492:apelin-13, Ala(13)-