Prevention of Fibrosis Progression in CCl₄-Treated Rats: Role of the Hepatic Endocannabinoid and Apelin Systems

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 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-LeuSer-His-Lys-Gly-Pro-Met-Pro-Ala (F13A) (75 g/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 ␤, ␣-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.

Adenoviral dominant-negative soluble PDGFRβ improves hepatic collagen, systemic hemodynamics, and portal pressure in fibrotic rats

“…The in vivo effects of PDGFR inhibitors are more complex, based on the crosstalk with other angiogenic factors [21,22]. We have recently reported that the stimulation of CB2 receptors, as well as the blockade of the hepatic apelin system activity, is able to attenuate collagen deposition in CCl 4 -treated rats through common mechanisms, such as the inhibition of PDGFRb expression [15]. In the current study, we investigated the role of PDGFRb in the physiopathological alterations that take place along the course of CCl 4 -induced experimental liver disease.…”

“…We have recently described that PDGFRb mRNA is overexpressed in the liver of rats subjected to chronic inhalation of carbon tetrachloride (CCl 4 ) as compared to control animals. Moreover, we have reported the antifibrogenic effects of endocannabinoids and apelin, which are associated with the inhibition of PDGFRb expression [15].…”

Cannabinoid CB1 receptor overactivity contributes to the pathogenesis of idiopathic pulmonary fibrosis

“…Endocannabinoids are bioactive lipids that act on cannabinoid receptors, CB 1 R and CB 2 R, that also recognize and mediate the effects of marijuana (16). Endocannabinoids acting via CB 1 R promote fibrosis progression in multiple organs, including liver (17)(18)(19)(20)(21), kidney (22,23), heart (24), and skin (25), and CB 1 R has been linked to radiation-induced PF in mice (26). In addition to promoting fibrosis, activation of CB 1 R is proinflammatory in chronic inflammatory diseases (27,28), whereas the brain-penetrant CB 1 R antagonist/inverse agonist rimonabant mitigates liver fibrosis in animal models (17).…”

Protection from Radiation-Induced Pulmonary Fibrosis by Peripheral Targeting of Cannabinoid Receptor-1

“…Both cannabinoid receptor-1 (CB 1 ) and cannabinoid receptor-2 (CB 2 ) were recently implicated in pathogenesis of skin (7)(8)(9)(10), liver (11)(12)(13)(14), cardiac (15), and renal (16) fibrotic proliferative diseases. However, the role of the endocannabinoid system in pulmonary fibrogenesis remains enigmatic.…”