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 CCl(4)-treated rats for 13 weeks.
Fibrosis-induced rats received a
CB2 receptor agonist (R,S)-3-(2-iodo-5-nitrobenzoyl)-1-(1-methyl-2-piperidinylmethyl)-1H-indole (
AM1241) (1 mg/kg b.wt.), an APJ antagonist [Ala(13)]-
apelin-13 sequence: Gln-
Arg-Pro-Arg-Leu-
Ser-His-
Lys-Gly-Pro-Met-Pro-Ala (F13A) (75 μg/kg b.wt.), or vehicle daily during the last 5 weeks of the CCl(4) 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 with control rats. However, fibrotic rats treated with either
AM1241 or F13A had reduced hepatic
collagen content, improved MAP and PP, ameliorated cell viability, and reduced angiogenesis and cell infiltrate compared with untreated fibrotic rats. These results were associated with attenuated induction of
platelet-derived growth factor receptor β, α-smooth muscle actin,
matrix metalloproteinases, and tissue inhibitors of
matrix metalloproteinase.
CB2 receptor stimulation or APJ blockade prevents
fibrosis progression in CCl(4)-treated rats. The mechanisms underlying these phenomena are coincident despite the marked dissimilarities between the CB2 and APJ signaling pathways, thus opening new avenues for preventing
fibrosis progression in
liver diseases.