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Blockade of the apelin–APJ system promotes mouse liver regeneration by activating Kupffer cells after partial hepatectomy

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

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.

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Abbreviations

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

ELISA:

Enzyme-linked immunosorbent assay

ERK:

Extracellular signal-related kinase

ExPH:

Extended partial hepatectomy

HGF:

Hepatocyte growth factor

IL-6:

Interleukin-6

JNK:

c-jun N-terminal kinase

LDLT:

Living donor liver transplantation

PCR:

Polymerase chain reaction

PH:

Partial hepatectomy

STAT3:

Signal transducer and activator of transcription 3

TNF:

Tumor necrosis factor

VEGF:

Vascular endothelial growth factor

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Acknowledgments

This work was supported in part by JSPS KAKENHI Grant Number 26861081.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan

    Shohei Yoshiya, Ken Shirabe, Daisuke Imai, Takeo Toshima, Yo-ichi Yamashita, Toru Ikegami, Shinji Okano, Tomoharu Yoshizumi, Hirofumi Kawanaka & Yoshihiko Maehara

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  1. Shohei Yoshiya
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  2. Ken Shirabe
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  3. Daisuke Imai
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Correspondence to Shohei Yoshiya.

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Yoshiya, S., Shirabe, K., Imai, D. et al. Blockade of the apelin–APJ system promotes mouse liver regeneration by activating Kupffer cells after partial hepatectomy. J Gastroenterol 50, 573–582 (2015). https://doi.org/10.1007/s00535-014-0992-5

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  • DOI: https://doi.org/10.1007/s00535-014-0992-5

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