Fc-apelin fusion protein attenuates lipopolysaccharide-induced liver injury in mice

Abstract

Apelin is a peptide hormone with anti-oxidative and anti-inflammatory activities and is proposed to be a potential therapeutic for many disease conditions, including sepsis. However, short in vivo half-life of the apelin peptide would limit its potential clinical applications. This study aims to investigate the effects of Fc-apelin, a novel long-acting apelin fusion protein, on lipopolysaccharide (LPS)-induced liver injury. Liver injury was induced by systemic injection of LPS in mice. Hepatoprotective activities of Fc-apelin against inflammation were evaluated in LPS mice and/or hepatoma Huh-7 cells with respect to serum ALT, apoptosis, oxidative stress, macrophage infiltration and gene expression. We found that LPS induced systemic inflammation and liver damage. Co-administration of Fc-apelin significantly attenuated serum ALT elevation, diminished LPS-induced apoptosis and ROS production in the liver and in Huh-7 cells, mitigated hepatic macrophage infiltration, and reduced TNFα and IL-6 gene expression. Collectively, Fc-apelin fusion protein exerts protective effects against LPS-induced liver damage and may serve as a potential therapeutic for endotoxin-induced liver injury.

Fc-Elabela fusion protein attenuates lipopolysaccharide-induced kidney injury in mice

“…Our in vitro experiments revealed that ELA was capable of suppressing LPS-induced ROS production [27] and apoptosis, and promoting cell survival in human kidney HK-2 cells. These observations are consistent with publications wherein exogenous administration of apelin or ELA can decrease inflammation in vitro and in vivo [14,34] and promote cell survival [19,35,36].…”

“…Fixed kidney tissues were processed routinely, embedded in paraffin, cut into 5-μm thickness slices and stained with Hematoxylin and Eosin (H/E). For immunohistochemistry (IHC), the paraffin-embedded sections were subjected to deparaffination, 3% H 2 O 2 treatment and antigen retrieval, and then sequential incubation with the primary antibody F4/80 (BM8, eBioscience) and HRP-conjugated goat anti-rabbit IgG (KPL, Gaithersburg, MD), as described previously [19]. Kidney tissue apoptosis was assessed by terminal deoxynucleotidyl transferase-mediated deoxyuridintriphosphate nick-end labeling (TUNEL) on tissue sections or HK2 cells grown on cover slides.…”

“…Many studies have shown that apelin can attenuate multiple organ injuries following hemorrhagic shock [ 15 ] and in sepsis [ 16–18 ]. We have previously reported that constant fragment (Fc)-apelin, a long-acting form of apelin, can ameliorate LPS-induced liver damage in mice [ 19 ]. Likewise, ELA has recently been reported to be protective against sepsis-induced organ damage [ 18 ].…”

Roles of the Hepatic Endocannabinoid and Apelin Systems in the Pathogenesis of Liver Fibrosis

“…These results suggest that the apelin system may interfere with hepatocyte proliferation after partial hepatectomy in mice. However, a recent study has shown that the administration of a long-acting apelin fusion protein resulted in attenuated hepatocyte damage, diminished apoptosis and ROS production in a mouse model of LPS-induced liver injury [196]. Altogether, these findings suggest that the apelin system may be involved in the processes of hepatic injury and regeneration, but these specific aspects need further investigation.…”

The apelinergic system: a perspective on challenges and opportunities in cardiovascular and metabolic disorders

“…Additional evidence of the deleterious impact of apelin disruption and/or antagonism of its receptor is exemplified by the serious adverse reactions sometimes observed using protamine (a submicromolar affinity competitive antagonist of the apelin receptor that reverses heparin anticoagulation), and by the occurrence of sudden rises in pulmonary arterial pressure, sustained hypotension, and impaired cardiac fractional shortening . Apelins can also potentially influence long‐term vascular remodeling by reducing inflammation and fibrosis …”