Abstract

Endocannabinoids behave as antifibrogenic agents by interacting with cannabinoid CB2 receptors, whereas the apelin (AP) system acts as a proangiogenic and profibrogenic mediator in the liver. This study assessed the effect of long-term stimulation of CB2 receptors or AP receptor (APJ) blockade on fibrosis progression in rats under a non-discontinued fibrosis induction program. The study was performed in control and CCl₄-treated rats for 13 weeks. Fibrosis-induced rats received a CB2 receptor agonist (AM1241, 1 mg/kg bwt), an APJ antagonist F13A (75 µg/kg bwt) or vehicle daily during the last 5 weeks of the CCl₄ inhalation program. Mean arterial pressure (MAP), portal pressure (PP), hepatic collagen content, angiogenesis, cell infiltrate and mRNA expression of a panel of fibrosis-related genes were measured in all animals. Fibrosis-induced rats showed increased hepatic collagen content, reduced MAP, portal hypertension and increased expression of the assessed messengers in comparison to control rats. However, fibrotic rats treated with both AM1241 or F13A had reduced hepatic collagen content, improved MAP and PP, ameliorated cell viability and reduced angiogenesis and cell infiltrate than untreated fibrotic rats. This was associated with an attenuated induction of PDGFRβ, α-SMA, MMPs and TIMPs. CB2 receptor stimulation or APJ blockade prevents fibrosis progression in CCl4-treated rats. The mechanisms underlying these phenomena are coincident in spite of the marked dissimilarities between the CB2 and APJ signaling pathways, thus opening new avenues for preventing fibrosis progression in liver diseases.