br The role of apelin in hepatic

The role of apelin in hepatic diseases The involvement of the apelin/APJ system in liver physiology and pathology has been proven in numerous studies (Table 6). For instance, in the experiment of Emam et al. [63] on rats suffering from hepatic injury, apelin decreased the levels of ALT, AST and LDH in serum. It also decreased caspase-3, TNF-a and MDA but increased GSH and CAT levels in the liver. The anti-inflammatory effect of apelin through abrogation of the pro-inflammatory cytokines (IL-6, IL-1b) and enhancement of the anti-inflammatory cytokine IL-10 was also observed [63]. In patients suffering from chronic hepatitis C, circulating serum apelin levels fluctuate and depend on the stage of the infection [64]. Also, apelin can affect glycogen synthesis in the hepatocytes. In an in vitro experiment on human HepG2 Phosphatase Inhibitor Cocktail 2 (100X in ddH2O) and primary mouse hepatocyte cells, it was found that apelin reduces glycogen synthesis in these liver cells and has anti-insulin resistance properties [65]. In addition, it has been noted that exogenous apelin can mediate tissue injury in the liver [66]. Yasuzaki et al. [67], in an experiment conducted on APJ−/− mice and wild-type mice with acute fulminant hepatitis induced by an i.p. injection of the purified hamster anti-mouse FAS monoclonal antibody Jo2, observed an increase in the apelin and APJ mRNA expression levels in the liver. Also, wild-type mice were characterized by massive hepatic haemorrhage, and increased plasma levels of AST, ALT, and caspase 3, 8 and 9 activities. Apart from this, phosphorylated JNK and c-jun proteins were observed in this group. In contrast, the livers from APJ−/− mice were preserved. These results indicate that the loss of APJ may confer resistance against Fas-mediated hepatocyte injury and suggest that apelin-APJ signalling may promote Fas-induced liver injury via JNK activation. Moreover, it is suggested that apelin/APJ signalling could participate in the formation of hepatic fibrosis or cirrhosis [67]. The overexpression of apelin receptor in human hepatocytes can be induced by pro-inflammatory and pro-fibrogenic factors (hypoxia, lipopolysaccharide, TNF α and angiotensin II). Stimulation of APJ by apelin results in activation of the synthesis of vascular endothelial growth factor type A, platelet-derived growth factor-BB and cell survival [68]. The protective effect of apelin on hepatic cells has been described by Huang et al. [69], who found that apelin inhibits lipid accumulation by reducing the cellular contents of triglycerides in human hepatoma cells (Hep3B) and in primary mouse hepatocytes. Apelin suppresses the expression of sterol regulatory element-binding protein 1c (SREBP-1c) and glycerol-3-phosphate acyltransferase (GPAT) as well, but the expression of peroxisome proliferator-activated receptor α (PPARα) in hepatocyte cells is related to the apelin concentration, which confirms the anti-steatotic effect of apelin in hepatocytes [69].
The role of apelin in kidney diseases During renal ischaemia/reperfusion (I/R) injury, apelin exhibits anti-inflammatory, anti-apoptotic and anti-fibrotic properties. In in vitro and in vivo experiments, it has been estimated that apelin reduces hypoxia inducible factor 1α (Hif1α), as well as ICAM-1 and MCP-1 in kidneys. Apelin also mediates histone methylation, increasing the levels of H3K4me2 and H3K79me1 in kidney cells (Table 7) [70]. In addition, in the experiment on mice with established type 1 diabetes, apelin did not affect glycaemia, body weight and blood pressure. It was noted, however, that apelin reduced renal hypertrophy, albuminuria and decreased glomerular enlargement and mesangial matrix deposition. Apelin also inhibited the expression of pro-inflammatory molecules, such as monocyte chemoattractant protein 1 (MCP1), vascular cell adhesion molecule 1 (VCAM1) and NF-κB activation [71]. It was also found that apelin can prevent cyclosporine-induced renal tubular injury in rats. Cyclosporine is used as an immunosuppressant agent after organ transplantation or for the treatment of autoimmune diseases. It is noted that renal tubular injury is one of the side effects of this compound. Apelin administered to rats suffering from this injury induced by cyclosporine increases urinary NGAL, eNOS and NFATc1 expression but reduces pNFATc1 expression in renal cortical tissues. Moreover, apelin may increase Na+-K+ATPase expression and decrease that of SGLT2 and GLUT2 [72]. Nevertheless, apelin may negatively influence podocyte proliferation. By evaluating these highly specialized cells obtained from mice suffering from diabetic nephropathy, Liu et al. have shown that apelin reduces autophagy-associated proteins (LC3, Beclin-1 and Atg5) and increases the number of apoptotic cells, which can lead to renal dysfunction in diabetic individuals [73].