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

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. 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. F13A-treated mice had significantly higher serum concentrations of tumor necrosis factor (TNF)-alpha 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-alpha and IL-6. Moreover, F13A-treated mice had a higher survival rate than untreated mice in the extended hepatectomy model. F13A treatment promotes early phase liver regeneration after hepatectomy by promoting the activation of Kupffer cells and increasing serum levels of TNF-alpha and IL-6. F13A treatment may become a therapeutic option to facilitate efficient liver regeneration after liver surgery.